Pyrrolopyrimidinone derivatives

Abstract

A compound having GSK-3 inhibitory activity. A1 and A3 are a single bond, an aliphatic hydrocarbon group; A2 and A4 are a single bond, CO, COO, CONR, O, OCO, NR, NRCO, NRCOO, etc.; G1 is a single bond, an aliphatic hydrocarbon, aromatic hydrocarbon, heterocyclic; G2 is H, an aliphatic hydrocarbon, an alicyclic hydrocarbon, an aromatic hydrocarbon, heterocyclic; A5 is a single bond, NR; R2 is H, halogen, an aliphatic hydrocarbon, alicyclic hydrocarbon, aromatic hydrocarbon, heterocyclic; A6 is a single bond, NR, CO, NRCO, NRCONR, CONR, COO, O, etc.; R3 is H, halogen, nitro, saturated aliphatic hydrocarbon, alicyclic hydrocarbon, aromatic hydrocarbon, heterocyclic; and R3 may be a trimethylsilyl, formyl, acyl, carboxyl, alkoxylcarbonyl, carbamoyl, alkylcarbamoyl, or cyano group when A6 is CR═CR or C≡C, wherein R is H or an lower aliphatic hydrocarbon group.

Description

TECHNICAL FIELD

The present invention relates to novel pyrrolopyrimidinone derivatives that have an action inhibiting glycogen synthase kinase-3 (GSK-3). More particularly, the invention relates to novel pyrrolo[3,2-d] pyrimidinone derivatives useful as pharmaceutical agents for treating and/or preventing disorders mediated by GSK-3 activity, particularly, impaired glucose tolerance, type I diabetes, type II diabetes, diabetic complications (retinopathy, nephropathy, neuropathy or great vessel hindrance), Alzheimer's disease, neurodegenerative diseases (AIDS encephalophy, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis or multiple sclerosis), bipolar affective disorder (manic depressive psychosis), traumatic cerebrospinal injury, epilepsy, obesity, atherosclerosis, hypertension, polycystic ovary syndrome, syndrome X, alopecia, inflammatory diseases (arthrosis deformans, rheumatism, atopic dermatitis, psoriasis, ulcerative colitis, Crohn's disease, sepsis or systemic inflammatory response syndrome), cancer and immunodeficiency.

BACKGROUND ART

GSK-3 is a serine/threonine protein kinase. Two isoforms, i.e., α and β, which are encoded by distinct genes, have been identified (see Trends Biochem. Sci., 1991, Vol. 16, p. 177).

Both GSK-3 isoforms have a monomeric structure and are constitutively active in resting cells. GSK-3 was originally identified as a kinase that inhibits glycogen synthase by direct phosphorylation (see Eur. J. Biochem., 1980, Vol. 107, p. 519). Upon insulin activation, GSK-3 is inactivated, thereby allowing the activation of glycogen synthase and possibly other insulin-dependent events, such as glucose transport. Also, it has been known that GSK-3 activity is inactivated by other growth factors, such as IGF-1 or FGF, through signaling from receptor tyrosine kinases (see Biochem. J., UK, 1993, Vol. 294, p. 625; Biochem. J., UK, 1994, Vol. 303, p. 21; Biochem. J., UK, 1994, Vol. 303, p. 27).

GSK-3 inhibitors are useful in the treatment of disorders that are mediated by GSK-3 activity. In addition, inhibition of GSK-3 mimics the activation of growth factor signaling pathways and consequently GSK-3 inhibitors are useful in the treatment of diseases in which such pathways are inactive. Examples of diseases that can be treated with GSK-3 inhibitors are described below.

Type I diabetes is induced due to autoimmune destruction of β cells as pancreatic insulin production cells, resulting in deficiency of insulin. From this, it is necessary for a type I diabetic patient to routinely be administered insulin for maintaining life. However, in current insulin therapy, strict control of the blood glucose levels like the ability of normal β cells cannot be reproduced. Thus, type I diabetes is liable to induce diabetic complications such as retinopathy, nephropathy, neuropathy, great vessels hindrance or the like.

Type II diabetes is a multifactorial disease. Hyperglycemia is due to insulin resistance in the liver, skeletal muscle and lipid tissues coupled with inadequate or defective secretion of insulin from pancreatic islets. As a result, diabetic complications such as retinopathy, nephropathy, neuropathy, or great vessels hindrance are induced. Skeletal muscle is the major site for insulin-stimulated glucose uptake, and glucose removed from the circulation is either metabolized through glycolysis and the TCA cycle or stored as glycogen. Muscle glycogen deposition plays a very important role in glucose homeostasis, and Type II diabetic subjects have defective muscle glycogen storage. GSK-3, which is known to phosphorylate glycogen synthase, inhibits the accumulation of glycogen in peripheral tissues and lowers the reactivity of insulin, leading to an increase in blood level of glucose.

Recently, it has been reported that the expression of GSK-3 is stimulated in skeletal muscles of type II diabetic patients, and the GSK-3α activity and insulin in skeletal muscles are inversely correlated (see Diabetes, USA, 2000, Vol. 49, p. 263). Where GSK-3β and active GSK-3β variants (S9A, S9E) are overexpressed in HEK-293 cells, the GSK activity is inhibited (see Proc. Natl. Acad. Sci., USA, 1996, Vol. 93, p. 10228). In CHO cells in which insulin receptor and insulin receptor substrate 1 (IRS-1) are expressed, overexpression of GSK-3β brings about a decrease in the insulin activity (see 8: Proc. Natl. Acad. Sci., USA, 1997, Vol. 94, 9660). Recent research carried out using C57BL/6J mice with pyknic type diabetes has clearly shown that GSK-3 activity stimulation and insulin resistance are correlated to the progress of type II diabetes (see Diabetes, USA, 1999, Vol. 48, p. 1662).

Conventionally, lithium salts have been known to have inhibitory effects of GSK-3 activity (see Proc. Natl. Acad. Sci., USA, 1996, Vol. 93, p. 8455). It has been reported that the therapy using the lithium salts lowers glucose levels in both type I and II diabetic patients, thereby alleviating the severity of the disease (see Biol. Trace Elements Res., 1997, Vol. 60, p. 131). However, lithium salts have also been found to exhibit various side effects on molecular targets other than GSK-3.

From the findings described above, it can be concluded that GSK-3 inhibitors are effective therapeutics for the treatment of impaired glucose tolerance, type I diabetes, type II diabetes and complications thereof.

It is also suggested that GSK-3 is associated with progress of Alzheimer's disease. The characteristic pathological features of Alzheimer's disease are senile plaques due to agglomeration of amyloid beta (Aβ) peptide and the formation of intracellular neurofibrillary tangles, leading to a large quantity of neuronal cell death, resulting in dementia. It is believed that GSK-3 involves abnormal phosphorylation of tau protein, which causes a neurofibrillary change in the course of progress of Alzheimer's disease (see Acta Neuropathol., 2002, Vol. 103, p. 91). Also, it has been found that GSK-3 inhibitors can prevent neuronal cell death (see J. Neurochem., 2001, Vol. 77, p. 94). Therefore, it is believed that the application of GSK-3 inhibitors to Alzheimer's disease can delay the progress of the disease. To date, therapeutic agents for Alzheimer's disease have mainly been used in conjunction with allopathy (see Expert Opin. Pharmacother., 1999, Vol. 1, p. 121). However, there is no known pharmaceutical agent that is effective in preventing neuronal cell death and delaying the onset or progress of Alzheimer's disease. These findings imply that GSK-3 inhibitors are effective pharmaceutical agents in alleviating the severity of Alzheimer's dementia.

There is a report that GSK-3 inhibitors suppress neuronal cell death, specifically, neuronal cell death due to overexcitement through glutamic acid (see Proc. Natl. Acad. Sci., USA, 1998, Vol. 95, p. 2642; J. Neurochem., 2001, Vol. 77, p. 94). This suggests that GSK-3 inhibitors are possibly useful in the treatment of bipolar affective disorder such as manic depressive psychosis, epilepsy or other degenerative brain injury or neurodegenerative diseases. Examples of the neurodegenerative disease include in addition to the Alzheimer's disease, AIDS encephalopathy, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, Pick's disease, progressive supranuclear palsy and so on. Also, overexcitement through glutamic acid is presumably a principal cause of brain dysfunction in stroke, including cerebral infarction, intracerebral hemorrhage and subarachnoid hemorrhage, traumatic cerebrospinal injury, bacteria/virus infectious disease, and GSK-3 inhibitors are expected to be effectively used in the treatment of these diseases. All of such diseases accompany neuronal death. Currently, no therapeutic agents for effectively suppressing neuronal death are available. Therefore, GSK-3 inhibitors are believed to become potentially effective pharmaceutical agents for the treatment of various kinds of neurodegenerative diseases, dipolar affective disorders (manic-depressive psychosis), epilepsy, stroke, traumatic cerebrospinal injury, and the like.

Several in vitro research results have led to a report that Wint10B potently suppresses the differentiation of preadipocytes to mature fat cells (see Science, 2000, Vol. 289, p. 950). GSK-3 specific inhibitors mimic Wint10B signaling in preadipocytes, that is, GSK-3 specific inhibitors stabilize free β-catenin in cytoplasm and suppress the induction of C/EBPα and PPARγ, thereby suppressing the formation of fat (see J. Biol. Chem, 2002, Vol. 277, p. 30998). GSK-3 inhibitors are therefore potentially useful as effective pharmaceutical compositions for treating obesity.

Also, β-catenin has been known to be a GSK-3 substrate in vivo. After phosphorylation by GSK-3, β-catenin is subjected to proteosome-dependent degradation (see EMBO J., 1998, Vol. 17, p. 1371). Meanwhile, transient β-catenin stabilization may lead to increase hair development (see Cell, 1998, Vol. 95, p. 605). Consequently, GSK-3 inhibitors are believed to be a useful medicament for the treatment of alopecia.

Further, research into GSK-3β knock out mouse-derived fibroblasts implies that GSK-3β regulates the activity of transcription factor NFκB to be at a positive level (see Nature, 2000, Vol. 406, p. 86). NFκB is in charge of cell responsiveness to numerous inflammatory stimuli. Thus, GSK-3 inhibitors may have beneficial effects in the treatment of inflammatory diseases such as arthrosis deformans, rheumatism, atopic dermatitis, psoriasis, ulcerative colitis, Crohn's Disease, sepsis, or systemic inflammatory response syndrome, by adjusting the NFκB activity to be at a negative level.

A transcription factor NF-AT is dephosphorylated by calcineurine and increases immunosuppressive response (see Science, 1997, Vol. 275, p. 1930). Conversely, GSK-3 phosphorylates NF-AT and transports the same from nuclei, thereby suppressing the expression of initial immune response gene. Thus, GSK-3 inhibitors could be useful to immunity activation for cancer immunotherapy.

Examples of materials that have conventionally been known to have GSK-3 inhibiting activity include hymenialdisine derivatives (see Chemistry & Biology, 2000, Vol. 7, p. 51, and WO01/41768 pamphlet), maleiimide derivatives (see Chemistry & Biology, 2000, Vol. 7, p. 793), paullone derivatives (see Eur. J. Biochem., 2000, Vol. 267, p. 5983 and WO01/60374 Pamphlet), purine derivatives (see WO98/16528 Pamphlet), pyrimidine and pyridine derivatives (see WO99/65897 Pamphlet), hydroxyflavone derivatives (see WO00/17184 Pamphlet), pyrimidone derivatives (see WO00/18758, WO01/70683, WO01/70729, WO01/70728, WO01/70727, WO01/70726, and WO01/70725 Pamphlets), pyrrole-2,5-dione derivatives (see WO00/21927 and WO01/74771 Pamphlets), diamino-1,2,4-triazolecarboxylic acid derivatives (see WO01/09106 Pamphlet), pyrazine derivatives (see WO01/44206 Pamphlet), bicyclic inhibitor (see WO01/44246 Pamphlet), indirubine derivatives (see WO01/37819 Pamphlet), carboxamide derivatives (see WO01/42224 Pamphlet), peptide inhibitors (see WO01/49709 Pamphlet), 2,4-diaminothiazole derivatives (see WO01/56567 Pamphlet), thiadiazolidindione derivatives (see WO01/85685 Pamphlet), aromatic amide derivatives (see WO01/81345 Pamphlet), and so on.

Also, the claims of WO02/085909 Pamphlet show a wide variety of compounds including pyrrolopyrimidine derivatives. However, bicyclic pyrrolopyrimidine derivatives actually synthesized are those having cyano groups at the 7-position of pyrrolopyrimidine ring and limited variety of substituents at other substitutable positions. In addition, while it discloses a method for assaying inhibitory activity of GSK-3 etc., it is silent about which compounds have such activities.

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide novel compounds which are specific to and capable of strongly inhibiting the activity of GSK-3 while being clinically applicable, and pharmaceutical compositions as GSK-3 inhibitors using them as effective ingredients.

Also, another object of the present invention is to provide an agent for treating or preventing a GSK-3-mediated disease.

Further, still another object of the present invention is to provide a method for treating a GSK-3-mediated disease.

The present inventors studied the above objects and consequently reached the following inventions.

Namely, the present invention provides a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof.

in the formula (I),

A¹ represents a single bond or represents a divalent acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms that links a nitrogen atom bonded to A¹ with A² on the same or different carbon atom;

A² represents a single bond or represents a group that links A¹ with G¹ in the form of

A¹-C(═O)-G¹,

A¹-C(═O)—O-G¹,

A¹-C(═O)—NR¹⁰¹-G¹,

A¹-C(═S)—NR¹⁰²-G¹,

A¹-C(═NR¹⁰³)-G¹,

A¹-O-G¹,

A¹-OC(═O)-G¹,

A¹-NR¹⁰⁴-G¹,

A¹-NR¹⁰⁵—C(═O)-G¹,

A¹-NR¹⁰⁶—S(═O)₂-G¹,

A¹-NR¹⁰⁷—C(═O)—O-G¹,

A¹-NR¹⁰⁸—C(═O)—NR¹⁰⁹-G¹,

A¹-NR¹¹⁰C(═S)-G¹,

A¹-NR¹¹¹—C(═S)—NR¹¹²-G¹,

A¹-S-G¹,

A¹—S(═O)-G¹,

A¹-S(═O)₂-G¹,

A¹-S(═O)₂—NR¹¹³-G¹,

A¹-CR¹¹⁴═CH-G¹,

A¹-CR¹¹⁵═CF-G¹,

A¹-CH═CR¹¹⁶-G¹, or

A¹—CF═CR¹¹⁷-G¹;

G¹ represents a single bond or represents a divalent group which is obtainable by removing two hydrogen atoms from any one of an optionally substituted alicyclic hydrocarbon group having 3 to 10 carbon atoms, an optionally substituted aromatic hydrocarbon having 6 to 14 carbon atoms, and an optionally substituted heterocyclic compound having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring.

A³ represents a single bond or represents an optionally substituted aliphatic hydrocarbon group having 1 to 10 carbon atoms that links G¹ with A⁴ on the same or different carbon atom;

A⁴ represents a single bond or represents a group that links A³ with G² in the form of

A³-C(═O)-G²,

A³-C(═O)—O-G²,

A³-C(═O)—NR¹²¹-G²,

A³-C(═S)—NR¹²²-G²,

A³-C(═NR¹²³)-G²,

A³—O-G²,

A³-O—C(═O)-G²,

A³-NR¹²⁴-G²,

A³—NR¹²⁵-C(═O)-G²,

A³-NR¹²⁶—S(═O)₂-G²,

A³-NR¹²⁷-C(═O)—O-G²,

A³-NR¹²⁸—C(═O)—NR¹²⁹-G²,

A³-NR¹³⁰-C(═S)-G²,

A³—NR¹³¹—C(═S)—NR¹³²-G²,

A³-S-G²,

A³-S(═O)-G²,

A³-S(═O)₂-G²,

A³-S(═O)₂—NR¹³³-G² or

A³-S(═O)₂—O-G²;

G² represents a hydrogen atom, an optionally substituted aliphatic hydrocarbon group having 1 to 10 carbon atoms, an optionally substituted alicyclic hydrocarbon group having 3 to 10 carbon atoms, an optionally substituted aromatic hydrocarbon group having 6 to 14 carbon atoms, or an optionally substituted heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring;

A⁵ represents a single bond or —NR²⁰¹—;

R² represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, an optionally substituted aliphatic hydrocarbon group having 1 to 10 carbon atoms, an optionally substituted alicyclic hydrocarbon group having 3 to 8 carbon atoms, an optionally substituted aromatic hydrocarbon group having 6 to 14 carbon atoms, or an optionally substituted heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring;

A⁶ represents a single bond or represents a group that links R³ with a carbon atom of a pyrrole ring to which A⁶ is bonded, in the form of

R³—NR³⁰¹-pyrrole ring,

R³—C(═O)-pyrrole ring,

R³—NR³⁰²—C(═O)-pyrrole ring,

R³—NR³⁰³—C(═S)-pyrrole ring,

R³—NR³⁰⁴—C(═O)—NR³⁰⁵-pyrrole ring,

R³—C(═O)—NR³⁰⁶-pyrrole ring,

R³—NR³⁰⁷—CH═N-pyrrole ring,

R³—C(═O)—O-pyrrole ring,

R³—O—C(═O)-pyrrole ring,

R³—O-pyrrole ring,

R³—S-pyrrole ring,

R³—S(═O)-pyrrole ring,

R³—S(═O)₂-pyrrole ring,

R³—CR³⁰⁸═CR³⁰⁹-pyrrole ring,

R³—C≡C-pyrrole ring, or

R³—S(═O)₂—C≡C-pyrrole ring;

R³ is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a nitro group, an optionally substituted saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms, an optionally substituted alicyclic hydrocarbon group having 3 to 8 carbon atoms, an optionally substituted aromatic hydrocarbon group having 6 to 14 carbon atoms, or an optionally substituted heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring;

A⁶-R³ may be a combination wherein A⁶ represents a group that links a carbon atom of a pyrrole ring to which A⁶ is bonded, with R³ in the form of R³—CR³⁰⁸═CR³⁰⁹-pyrrole ring or R³—C≡C-pyrrole ring, and R³ represents a trimethylsilyl group, a formyl group, an optionally substituted C₂-C₇ acyl group, a carboxyl group, a C₂-C₇ alkoxycarbonyl group, a carbamoyl group, an optionally substituted C₂-C₇ alkylcarbamoyl group, or a cyano group;

R¹⁰¹˜R¹¹⁷, R¹²¹˜R¹³³, R²⁰¹ and R³⁰¹˜R³⁰⁹ are each independently a hydrogen atom or an aliphatic hydrocarbon group having 1 to 4 carbon atoms.

However, when both A¹ and A³ represent acyclic alphatic hydrocarbon groups, at least one of A² or G¹ is not a single bond.

In addition, the present invention provides a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof represented by the formula (I); and a pharmaceutically acceptable carrier.

Further, the present invention provides a GSK-3 inhibitor comprising the compound or a pharmaceutically acceptable salt thereof represented by the formula (I) as an effective ingredient.

Furthermore, the present invention provides an agent for treating or preventing a GSK-3-mediated disease, comprising the compound or a pharmaceutically acceptable salt thereof represented by the formula (I) as an effective ingredient.

Furthermore, the present invention provides a method for treating a GSK-3-mediated disease, comprising a step of injecting the compound or a pharmaceutically acceptable salt thereof represented by the formula (I) in treatment valid amount to a patient.

Note that, in A¹-G² portion in the formula (1), there also exists a case where different combinations consequently represent the same substituent according to the combination of A¹, A², G¹, A³, A⁴, and G², and combinations containing also substituents of them where they may have substituents. However, the scope of the present invention will not become clear due to this.

Note that the corresponding pyrimidine-thione derivative can be derived from the compound represented by the formula (I) of the present invention through the pyrrolopyrimidine derivative represented by the following formula (II).

in formula (I), A¹, A², A³, A⁴, A⁵, A⁶, G¹, G², R² and R³ are as defined in the formula (I); and X¹ is a chlorine atom, a bromine atom, an iodine atom, a C₂-C₁₀ acylthio group, a C₂-C₈ alkoxymethylthio group, a C₁-C₈ alkyl group, or a C₁-C₈ arylsulfonyloxy group).

Still further, the present invention is a compound represented by the following formula (Ic) which can be used as the manufacture intermediate of the pyrrolopyrimidinone derivative represented by the formula (I)

in formula (Ic), A¹, A², A³, A⁴, A⁵, A⁶, G¹, G², R², and R³ are as defined in the formula (I); and Q represents an optionally substituted a C₂-C₁₀ acyl group, an optionally substituted C₂-C₁₀ alkoxymethyl group or an optionally substituted benzyl group.

BEST MODE FOR WORKING THE INVENTION

The “acyclic aliphatic hydrocarbon group” in the present description contains a straight or branched acyclic aliphatic hydrocarbon group. It may be saturated so far as it is the acyclic aliphatic hydrocarbon group as well and may have one or more double bonds or triple bonds in a chemically possible range.

The “alkyl group” in the present description represents a straight or branched saturated acyclic aliphatic hydrocarbon group, for example methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, isobutyl, s-butyl, t-butyl, isopentyl, neopentyl, t-pentyl, or isohexyl.

The “pyridyl group” in the present description contains N-oxide thereof as well.

The term “cycloalkyl group” in the present description means a saturated alicyclic hydrocarbon group, for example cyclopropyl, cyclobutyl, or cyclohexyl.

The term “heterocyclic” in the present description is not particularly limited so far as it can chemically stably exist if it is monocyclic to tricyclic having 1 to 4 atoms selected from among a group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom, in the ring, but preferably monocyclic or bicyclic having carbon atoms not more than 9 containing 1 to 3, preferably 1 or 2 atoms selected from among a group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom, in the ring.

In the formula (I), A¹ represents a single bond or represents a divalent acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms that links a nitrogen atom bonded to A¹ with A² on the same or different carbon atoms.

Examples of the acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms in A¹ include divalent groups obtainable by removing two hydrogen atoms from methane, ethane, propane, butane, 2-methylpropane, pentane, 2-methylbutane, 2,2-dimethylpropane, hexane, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane, 2,3-dimethylbutane and 2,2,3-trimethylpropane.

Examples of suitable A¹ include —CH₂—, —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —(CH₂—)₅—, —(CH₂)₆—, —CH(CH₃)—, —CH(CH₃)CH₂—, —CH(CH₃)CH(CH₃)—, —C(CH₃)₂CH₂—, —CH(CH₃)(CH₂)₂—, CH₂CH(CH₃)CH₂—, —CH(CH₃)CH(CH₃)CH₂—, —CH(CH₃)CH₂CH(CH₃)—, —CH₂C(CH₃)₂CH₂—, —CH(CH₃)C(CH₃)₂CH₂—, —CH(CH₂CH₃) (CH₂)₂—, —CH₂CH(CH₂CH₃)CH₂—, —CH(CH₂CH₃)CH(CH₃)CH₂—, —CH(CH₃)CH(CH₂CH₃)CH₂—, —CH(CH₂CH₃)CH₂CH(CH₃)—, —CH(CH₃) (CH₂)₃—, —CH₂CH(CH₃) (CH₂)₂—, —CH(CH₃)CH(CH₃) (CH₂)₂—, —CH(CH₃)CH₂CH(CH₃)CH₂—, —CH₂CH(CH₃)CH(CH₃)CH₂—, —CH₂C(CH₃)₂(CH₂)₂—, —CH(CH₃)C(CH₃)₂CH₂—, —CH(CH₂CH₃)(CH₂)₃—, —CH₂CH(CH₂CH₃) (CH₂)₂—, —CH(CH₃) (CH₂)₄—, —CH₂CH(CH₃) (CH₂)₃—, and —(CH₂)₂CH(CH₃) (CH₂)₂—. Examples of preferred A¹ include —CH₂—, —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —CH(CH₃)CH₂—CH(CH₃)CH(CH₃)—, —CH(CH₃) (CH₂)₂—CH₂CH(CH₃)CH₂—, and —CH(CH₃)CH(CH₃)CH₂—. More preferred examples of A¹ include —CH₂—, —(CH₂)₂—, and —(CH₂)₃—. As more preferable examples of A¹, —(CH₂)₂— may be mentioned.

In the formula (I), A² represents a single bond or represents a group that links A¹ and G¹ in the form of A¹-C(═O)-G¹, A¹-C(═O)—O-G¹, A¹-C(═O)—NR¹⁰¹-G¹, A¹—C(═S)—NR¹⁰²-G A¹-C(═NR¹⁰³)-G¹, A¹-O-G¹, A¹-O—C(═O)-G¹, A¹-NR¹⁰⁴-G¹, A¹-NR¹⁰⁵—C(═O)-G¹, A¹-NR¹⁰⁶-S(═O)₂-G¹, A¹-NR¹⁰⁷—C(═O)—O-G¹, A¹-NR¹⁰⁸—C(═O)—NR¹⁰⁹-G¹, A¹-NR¹¹⁰—C(═S)-G¹, A¹-NR¹¹¹—C(═S)—NR¹¹²-G¹, A¹-S-G¹, A¹-S(═O)-G¹, A¹-S(═O)₂-G¹, A¹-S(═O)₂—NR¹¹³-G¹, A¹-CR¹¹⁴═CH-G¹, A¹-CR¹¹⁵═CF-G¹, A¹-CH═CR¹¹⁶-G¹ or A¹-CF═CR¹¹⁷-G¹ (R¹⁰¹˜R¹¹⁷ are independently a hydrogen atom or a acyclic aliphatic hydrocarbon group having 1 to 4 carbon atoms).

When A¹ and G¹ are linked to each other in the form of A¹-C(═O)—NR¹⁰¹-G¹, examples of the C₁-C₄ aliphatic hydrocarbon group of R¹⁰¹ include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, cyclopropylmethyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-propynyl, 2-butynyl and 3-butynyl group. The C₁-C₄ acyclic aliphatic hydrocarbon group may also be substituted with one or more substituents selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a hydroxy group, a methoxy group, an ethoxy group, an oxo group, a cyano group, a carboxyl group, a carbamoyl group, an amino group, a sulfo group, and a phenyl group. Examples of preferred R¹⁰¹ include a hydrogen atom, methyl, ethyl, and propyl group. Particularly, a hydrogen atom is preferred.

When A¹ and G¹ are linked to each other in the form of A¹-C(═S)—NR¹⁰²-G¹, examples of the C₁-C₄ aliphatic hydrocarbon group of R¹⁰² include the same as those selected as the examples of R¹⁰¹. Examples of preferred R¹⁰² include a hydrogen atom, methyl, ethyl, and propyl group. Particularly, a hydrogen atom is preferred.

When A¹ and G¹ are linked to each other in the form of A¹-C(═NR¹⁰³)-G¹, examples of the C₁-C₄ aliphatic hydrocarbon group of R¹⁰³ include the same as those selected as the examples of R¹⁰¹. Examples of preferred R¹⁰³ include a hydrogen atom, methyl, ethyl, and propyl group. Particularly, a hydrogen atom is preferred.

When A¹ and G¹ are linked to each other in the form of A¹-NR¹⁰⁴-G¹, examples of the C₁-C₄ aliphatic hydrocarbon group of R¹⁰⁴ include the same as those selected as the examples of R¹⁰¹. Examples of preferred R¹⁰⁴ include a hydrogen atom, methyl, ethyl, and propyl group. Particularly, a hydrogen atom is preferred.

When A¹ and G¹ are linked to each other in the form of A¹-NR¹⁰⁵-C(═O)-G¹, examples of the C₁-C₄ acyclic aliphatic hydrocarbon group of R¹⁰⁵ include the same as those selected as the examples of R¹⁰¹. Examples of preferred R¹⁰⁵ include a hydrogen atom, methyl, ethyl, and propyl group. Particularly, a hydrogen atom is preferred.

When A¹ and G¹ are linked to each other in the form of A¹-NR¹⁰⁶—S(═O)₂-G¹, examples of the C₁-C₄ aliphatic hydrocarbon group of R¹⁰⁶ include the same as those selected as the examples of R¹⁰¹. Examples of preferred R¹⁰⁶ include a hydrogen atom, methyl, ethyl, and propyl group. Particularly, a hydrogen atom is preferred.

When A¹ and G¹ are linked to each other in the form of A¹-NR¹⁰⁷—C(═O)—O-G¹, examples of the C₁-C₄ aliphatic hydrocarbon group of R¹⁰⁷ include the same as those selected as the examples of R¹⁰¹. Examples of preferred R¹⁰⁷ include a hydrogen atom, methyl, ethyl, and propyl group. Particularly, a hydrogen atom is preferred.

When A¹ and G¹ are linked to each other in the form of A¹-NR¹⁰⁸—C(═O)NR¹⁰⁹-G¹, examples of such preferred C₁-C₄ aliphatic hydrocarbon group of R¹⁰⁸ and R¹⁰⁹ include the same as those selected as the examples of R¹⁰¹. Examples of preferred R¹⁰⁸ and R¹⁰⁹ include a hydrogen atom, methyl, ethyl, and propyl group. Particularly, a hydrogen atom is preferred.

When A¹ and G¹ are linked to each other in the form of A¹-NR¹¹⁰—C(═S)-G¹, examples of such preferred C₁-C₄ aliphatic hydrocarbon group of R¹¹⁰ include the same as those selected as the examples of R¹⁰¹. Examples of preferred R¹¹⁰ include a hydrogen atom, methyl, ethyl, and propyl group. Particularly, a hydrogen atom is preferred.

When A¹ and G¹ are linked to each other in the form of A¹-NR¹¹¹—C(═S)—NR¹¹²-G¹, examples of the C₁-C₄ aliphatic hydrocarbon group of R¹¹¹ and R¹¹² include the same as those selected as the examples of R¹⁰¹. Examples of preferred R¹¹¹ and R¹¹² include a hydrogen atom, methyl, ethyl, and propyl group. Particularly, a hydrogen atom is preferred.

When A¹ and G¹ are linked to each other in the form of A¹-S(═O)₂—NR¹¹³-G¹, examples of the C₁-C₄ aliphatic hydrocarbon group of R¹¹³ include the same as those selected as the examples of R¹⁰¹. Examples of preferred R¹¹³ include a hydrogen atom, methyl, ethyl, and propyl group. Particularly, a hydrogen atom is preferred.

When A¹ and G¹ are linked to each other in the form of A¹—CR¹¹⁴═CR¹¹⁵-G¹, examples of the C₁-C₄ aliphatic hydrocarbon group of R¹¹⁴ and R¹¹⁵ include the same as those selected as the examples of R¹⁰¹. Examples of preferred R¹¹⁴ and R¹¹⁵ include a hydrogen atom, methyl, ethyl, and propyl group. Particularly, a hydrogen atom is preferred.

When A¹ and G¹ are linked to each other in the form of A¹-CF═CR¹¹⁷-G¹, examples of the C₁-C₄ aliphatic hydrocarbon group of R¹¹⁷ include the same as those selected as the examples of R¹⁰¹. Examples of preferred R¹¹⁷ include a hydrogen atom, methyl, ethyl, and propyl group. Particularly, a hydrogen atom is preferred.

When A¹ and G¹ are linked to each other in the form of A¹-CF═CR¹¹⁷-G¹, examples of the C₁-C₄ aliphatic hydrocarbon group of R¹¹⁷ include the same as those selected as the examples of R¹⁰¹. Examples of preferred R¹¹⁷ include a hydrogen atom, methyl, ethyl, and propyl group. Particularly, a hydrogen atom is preferred.

Examples of preferred A² include groups that link A¹ and G¹ in the form of A¹-C(═O)-G¹, A¹-C(═O)—NR¹⁰¹-G¹, A¹-O-G¹, A¹-NR¹⁰⁴-G¹, A¹-NR¹⁰⁵—C(═O)-G¹, A¹-NR¹⁰⁸—C(═O)—NR¹⁰⁹-G¹, A¹—NR¹¹⁰—C(═S)-G¹ and A¹-NR¹¹¹—C(═S)NR¹¹²-G¹, especially preferably in the form of A¹-C(═O)-G¹, A¹-C(═O)—NR¹⁰¹-G¹, A¹-NR¹⁰⁴-G¹, A¹—NR¹⁰⁵—C(═O)-G¹, A¹-NR¹⁰⁸—C(═O)—NR¹⁰⁹-G¹, and A¹-NR¹¹⁰—C(═S)-G¹. Among them, examples of more preferred A² include groups that link A¹ and G¹ in the form of A¹-C(═O)—NR¹⁰¹-G¹, A¹-NR¹⁰⁵—C(═O)-G¹, and A¹-NR¹⁰⁸—C(═O)—NR¹⁰⁹-G¹. Here, forms of linkage exemplified as preferred and more preferred A² are preferably combined with structures in which A¹ exists in the form of —(CH₂)₂— or —(CH₂)₃— in the formula (I).

In the formula (I), A³ represents a single bond or represents an optionally substituted divalent aliphatic hydrocarbon group having 1 to 10 carbon atoms that links G¹ and A⁴ on the same or different carbon atoms.

Examples of the acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms of A³ include, in addition to the same as those selected as the examples of A¹, —CH═CH—, —C(CH₃)═CH—, —C(CH₃)═C(CH₃)—, —C(CH₂CH₃)═CH—, —C(CH₂CH₃)═C(CH₃)—, —C(CH₂CH₃)═C(CH₂CH₃)—, —C(CH₂CH₂CH₃)═CH—, —C(CH₂CH₂CH₃)═C(CH₃)—, —CH═CHCH₂—, —C(CH₃)═CHCH₂—, —CH═C(CH₃)CH₂—, —CH═CHCH(CH₃)—, —C(CH₃)═C(CH₃)CH₂—, C(CH₃)═CHCH(CH₃)—, —C(CH₃)═C(CH₃)CH(CH₃)—, —C(CH₃)═CHC(CH₃)₂—, —C(CH₂CH₃)═CHCH₂—, —CH═C(CH₂CH₃)CH₂—, —CH═CHCH(CH₂CH₃)—, —C(CH₂CH₃)═C(CH₃)CH₂—, —C(CH₂CH₃)═CHCH(CH₃)—, —C(CH₃)═C(CH₂CH₃)CH₂—, —CH═C(CH₂CH₃)CH(CH₃)—, —CH═CHCH(CH₂CH₃)—, —C(CH₃)═CHCH(CH₂CH₃)—, —CH═C(CH₃)CH(CH₂CH₃)—, —CH═CH(CH₂)₂—, —C(CH₃)═CH(CH₂)₂—, —CH═C(CH₃)(CH₂)₂—, —CH═CHC(CH₃)CH₂—, —C H═CHCH₂CH(CH₃)—, —C(CH₃)═C(CH₃)(CH₂)₂—, —C(CH₃)═CHCH(CH₃)CH₂—, —C(CH₃)═CHCH₂CH(CH₃)—, —CH₂CH═CHCH₂—, —CH(CH₃)CH═CHCH₂—, —CH₂C(CH₃)═CHCH₂—, —CH(CH₃)C(CH₃)═CHCH₂—, —CH(CH₃)CH═CHCH(CH₃)—, —CH(CH₃)CH═C(CH₃)CH₂—, —CH₂C(CH₃)═C(CH₃)CH₂—, —CH(CH₂CH₃)CH═CHCH₂—, and —CH₂C(CH₂CH₃)═CHCH₂—.

Substituents of divalent substituted aliphatic hydrocarbon group having 1 to 10 carbon atoms of A³ include a hydrocarbon group having 1 to 6 carbon atoms, an alicyclic hydrocarbon group having 3 to 6 carbon atoms, a halogen atom, an alkoxy group having 1 to 6 carbon atoms, a phenoxy group, an amino group, or an alkyl amino group having 1 to 6 carbon atoms.

Examples of such preferred A³ include a single bond, —CH₂—, —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —CH(CH₃)CH₂—, —CH(CH₃)CH(CH₃)—, —CH(CH₃) (CH₂)₂—, —CH═CH— and —CH═CHCH₂—. Further, examples of more preferred A³ include a single bond, —CH₂—, —(CH₂)₂— and —(CH₂)₃—. The same applies when A³ is substituted, but a single bond is excluded.

In the formula (I), A⁴ represents a single bond or represents a group that links A³ and G² in the form of A³-C(═O)-G², A³-C(═O)—O-G², A³-C(═O)—NR¹²¹-G², A³-C(═S)—NR¹²²-G², A³-C(═NR¹²³)-G², A³-O-G², A³-O—C(═O)-G², A³-NR¹²⁴-G², A³-NR¹²⁵—C(═O)-G², A³-NR¹²⁶—S(═O)₂-G², A³-NR¹²⁷—C(═O)—O-G², A³-NR¹²⁸—C(═O)—NR¹²⁹-G², A³—NR¹³⁰—C(═S)-G², A³-NR¹³¹—C(═S)—NR¹³²-G², A³-S-G², A³-S(═O)-G², A³-S(═O)₂-G², A³-S(═O)₂—NR¹³³-G² or A³-S(═O)₂—O-G² (in which R¹²¹ through R¹³³ are each independently a hydrogen atom or a acyclic aliphatic hydrocarbon group having 1 to 4 carbon atoms).

When A³ and G² are linked to each other in the form of A³-C(═O)—NR¹²¹-G², examples the C₁-C₄ acyclic aliphatic hydrocarbon group of R¹²¹ include the same as those selected as the examples of R¹⁰¹ in A². Examples of preferred R¹²¹ include a hydrogen atom, methyl, ethyl, and propyl group. Particularly, a hydrogen atom is preferred.

When A³ and G² are linked to each other in the form of A³-C(═S)—NR¹²²-G², examples of the C₁-C₄ acyclic aliphatic hydrocarbon group of R¹²² include the same as those selected as the examples of R¹⁰¹ in A². Examples of preferred R¹²² include a hydrogen atom, methyl, ethyl, and propyl group. Particularly, a hydrogen atom is preferred.

When A³ and G² are linked to each other in the form of A³-C(═NR¹²³)-G², examples of the C₁-C₄ acyclic aliphatic hydrocarbon group of R¹²³ include the same as those selected as the examples of R¹⁰¹ in A². Examples of preferred R¹²³ include a hydrogen atom, methyl, ethyl, and propyl group. Particularly, a hydrogen atom is preferred.

When A³ and G² are linked to each other in the form of A³-NR¹²⁴-G², examples of the C₁-C₄ acyclic aliphatic hydrocarbon group of R¹²⁴ include the same as those selected as the examples of R¹⁰¹ in A². Examples of preferred R¹²⁴ include a hydrogen atom, methyl, ethyl, and propyl group. Particularly, a hydrogen atom is preferred.

When A³ and G² are linked to each other in the form of A³-NR¹²⁵—C(═O)-G², examples of the C₁-C₄ aliphatic hydrocarbon group of R¹²⁵ include the same as those selected as the examples of R¹⁰¹ in A². Examples of preferred R¹²⁵ include a hydrogen atom, methyl, ethyl, and propyl group. Particularly, a hydrogen atom is preferred.

When A³ and G² are linked to each other in the form of A³-NR¹²⁶—S(═O)₂-G², examples of the C₁-C₄ acyclic aliphatic hydrocarbon group of R¹²⁶ include the same as those selected as the examples of R¹⁰¹ in A². Examples of preferred R¹²⁶ include a hydrogen atom, methyl, ethyl, and propyl group. Particularly, a hydrogen atom is preferred.

When A³ and G² are linked to each other in the form of A³-NR¹²⁷—C(═O)—O-G², examples of the C₁-C₄ acyclic aliphatic hydrocarbon group of R¹²⁷ include the same as those selected as the examples of R¹⁰¹ in A². Examples of preferred R¹²⁷ include a hydrogen atom, methyl, ethyl, and propyl group. Particularly, a hydrogen atom is preferred.

When A³ and G² are linked to each other in the form of A³-NR¹²⁸—C(═O)—NR¹²⁹-G², examples of the C₁-C₄ aliphatic hydrocarbon group of R¹²⁸ and R¹²⁹ include the same as those selected as the examples of R¹⁰¹ in A². Examples of preferred R¹²⁸ and R¹²⁹ include a hydrogen atom, methyl, ethyl, and propyl group. Particularly, a hydrogen atom is preferred.

When A³ and G² are linked to each other in the form of A³-NR¹³⁰—C(═S)-G², examples of the C₁-C₄ acyclic aliphatic hydrocarbon group of R¹³⁰ include the same as those selected as the examples of R¹⁰¹ in A². Examples of preferred R¹³⁰ include a hydrogen atom, methyl, ethyl, and propyl group. Particularly, a hydrogen atom is preferred.

When A³ and G² are linked to each other in the form of A³-NR¹³¹—C(═S)—NR¹³²-G², examples of the C₁-C₄ acyclic aliphatic hydrocarbon group of R¹³¹ and R¹³² include the same as those selected as the examples of R¹⁰¹ in A². Examples of preferred R¹³¹ and R¹³² include a hydrogen atom, methyl, ethyl, and propyl group. Particularly, a hydrogen atom is preferred.

When A³ and G² are linked to each other in the form of A³-S(═O)₂—NR¹³³-G², examples of the C₁-C₄ acyclic aliphatic hydrocarbon group of R¹³³ include the same as those selected as the examples of R¹⁰¹ in A². Examples of preferred R¹³³ include a hydrogen atom, methyl, ethyl, and propyl group. Particularly, a hydrogen atom is preferred.

Examples of such A⁴ include a single bond and a group that links A³ and G² in the form of A³-C(═O)-G², A³-C(═O)—O-G², A³—C(═O)—NR¹²¹-G², A³—O-G², A³—NR¹²⁴-G², A³—NR¹²⁵—C(═O)-G², A³-S(═O)₂-G² or A³-S(═O)₂—O-G².

In the formula (I), G¹ represents a single bond or a divalent group obtainable by removing two hydrogen atoms from any of groups consisting of a substituted or unsubstituted alicyclic hydrocarbon group having 3 to 10 carbon atoms, a substituted or unsubstituted aromatic hydrocarbon group having 6 to 14 carbon atoms, and a heterocyclic compound having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on its substituted or unsubstituted ring.

In the formula (I), when G¹ represents a substituted or unsubstituted divalent alicyclic hydrocarbon group having 3 to 10 carbon atoms, examples of the alicyclic hydrocarbon group having 3 to 10 carbon atoms include cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cycloheptane, cycloheptene, cyclooctane, bicyclo[2.2.1]heptane, bicyclo[2.2. 1]heptene, bicyclo[3.1.1]heptane and bicyclo[2.2. 2]octane. Examples of such preferred C₃-C₁₀ alicyclic hydrocarbon of G¹ include monocyclic alicyclic hydrocarbon group having 3 to 6 carbon atoms such as cyclopropane, cyclopentane, cyclohexane and the like.

Examples of the substituent for the substituted alicyclic hydrocarbon group having 3 to 10 carbon atoms of G¹ include: a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a hydroxy group, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy, t-pentyloxy, hexyloxy, isohexyloxy, 2-methyl-pentyloxy, 1-ethylbutoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cyclopropylmethyloxy, cyclopropylethyloxy, cyclopentylmethyloxy and cyclohexylmethyloxy or another C₁-C₇ alkoxy group consisting of a straight or branched alkyl, cycloalkyl and oxy group, ethylene dioxy or another C₁-C₄ alkylenedioxy group, phenoxy, 1-naphthoxy and 2-naphthoxy or another C₆-C₁₀ aryloxy group, benzyloxy, α-phenethyloxy, β-phenethyloxy and phenylpropyloxy or another C₇-C₉ aralkoxy group, acetoxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy, pivaloyloxy and hexanoyloxy or another C₂-C₇ acyloxy group, oxo, methylsulfonyloxy, ethylsulfonyloxy, propylsulfonyloxy, butylsulfonyloxy and t-butylsulfonyloxy or another C₁-C₆ alkylsulfonyloxy group consisting of a straight or branched alkyl and sulfonyloxy, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaroyl and hexanoyl or another C₂-C₇ acyl group, carboxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, s-butoxycarbonyl and t-butoxycarbonyl or another C₂-C₇ alkoxycarbonyl group consisting of a straight or branched alkyl and oxycarbonyl group, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, N-isobutylcarbamoyl, N-s-butylcarbamoyl, N-t-butylcarbamoyl, N-pentylcarbamoyl, N-cyclopropylcarbamoyl, N-cyclobutylcarbamoyl, N-cyclopentylcarbamoyl, N-cyclohexylcarbamoyl, N-cycloheptylcarbamoyl, N-cyclopropylmethylcarbamoyl, N,N-dimethylcarbamoyl, N-ethyl-N-methylcarbamoyl, N,N-diethylcarbamoyl and N,N-dipropylcarbamoyl or another C₂-C₇ alkylcarbamoyl group consisting of a straight or branched alkyl, cycloalkyl and carbamoyl group, amino, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, s-butylamino, t-butylamino, pentylamino, hexylamino, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, cyclopropylmethylamino, dimethylamino, N-ethylmethylamino, diethylamino, N-methylpropylamino, N-methylisopropylamino, N-methylbutyl-amino, N-methyl-t-butylamino, N-ethylisopropylamino, dipropylamino, diisopropylamino and ethylbutylamino or another C₁-C₆ alkylamino group consisting of a straight or branched alkyl, cycloalkyl and amino group, acetylamino, propionylamino, butyrylamino, isobutyrylamino, valerylamino and hexanoylamino or another C₂-C₇ acylamino group, methoxycarbonylamino, ethoxycarbonylamino and t-butoxycarbonylamino or another C₂-C₈ alkoxycarbonylamino group, methylsulfonylamino, ethylsulfonylamino, butylsulfonylamino and t-butylsulfonylamino or another C₁-C₆ alkylsulfonylamino group, a cyano group, a nitro group, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, s-butylthio, t-butylthio, pentylthio and hexylthio or another C₁-C₆ alkylthio group, methylsulfynyl, ethylsulfynyl, propylsulfynyl, isopropylsulfynyl, butylsulfynyl, isobutylsulfynyl, s-butylsulfynyl, t-butylsulfynyl, pentylsulfynyl and cyclopentylsulfynyl or another C₁-C₆ alkylsulfynyl group consisting of a straight or branched alkyl, cycloalkyl and sulfynyl group, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butyl-sulfonyl, isobutylsulfonyl, s-butylsulfonyl, t-butylsulfonyl, pentylsulfonyl, hexylsulfonyl, cyclopentylsulfonyl and cyclohexylsulfonyl or another C₁-C₆ alkylsulfonyl group consisting of a straight or branched alkyl, cycloalkyl and sulfonyl group, a sulfo group, a sulfamoyl group, methylaminosulfonyl, ethylaminosulfonyl, propylaminosulfonyl, isopropylaminosulfonyl, butylaminosulfonyl, isobutylamino-sulfonyl, s-butylaminosulfonyl, pentylaminosulfonyl, dimethylaminosulfonyl, N-ethyl-N-methylaminosulfonyl, diethylaminosulfonyl, dipropylaminosulfonyl, cyclopropyl-aminosulfonyl, cyclopentylaminosulfonyl, cyclohexylamino-sulfonyl and cyclopropylmethylaminosulfonyl or another C₁-C₆ aminosulfonyl group consisting of a straight or branched alkyl, a cycloalkyl and aminosulfonyl group, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl or another alicyclic hydrocarbon group having 3 to 6 carbon atoms, methyl, ethyl, vinyl, ethynyl, propyl, 1-propenyl, 2-propenyl, isopropyl, isopropenyl, 1-propynyl, 2-propynyl, butyl, isobutyl, s-butyl, t-butyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-butynyl, 2-butynyl, pentyl, isopentyl, neopentyl, t-pentyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, hexyl, 5-hexenyl, 4-methyl-3-pentenyl, isohexyl, 2-methylpentyl and 1-ethylbutyl or another aliphatic hydrocarbon group having 1 to 6 carbon atoms which may contain a straight or branched unsaturated bond.

As the substituent of the substituted alicyclic hydrocarbon group having 3 to 10 carbon atoms as G¹, a C₁-C₇ alkoxy group, a C₂-C₇ acyl group, a C₂-C₇ alkylcarbamoyl group, a C₁-C₆ alkylamino group, a C₂-C₇ acylamino group, an alicyclic hydrocarbon group having 3 to 6 carbon atoms or an aliphatic hydrocarbon group having 1 to 6 carbon atoms, may further be substituted with (one or more substituents selected from the group consisting of a fluorine atom; a chlorine atom; a bromine atom; an iodine atom; a hydroxy group; a C₁-C₆ alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy or cyclopropyloxy; a C₂-C₇ acyl group such as methoxymethyloxy group, 2-methoxyethoxy group, formyl group, trifluoroacetyl group, acetyl, propionyl, butyryl, isobutyryl, valeryl or isovaleryl; an oxo group; a carboxyl group; a C₂-C₇ alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl or t-butoxycarbonyl; a carbamoyl group; a C₂-C₇ alkylcarbamoyl group such as N-methylcarbamoyl, N,N-dimethylcarbamoyl, N-ethylcarbamoyl, N-ethyl-N-methylcarbamoyl, N,N-diethyl-carbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbambyl, N-cyclopropylcarbamoyl or N-cyclopropyl-methylcarbamoyl; an amino group; a C₁-C₆ alkylamino group such as methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, N-ethylmethylamino, diethylamino, N-methyl-propylamino, N-methylisopropylamino, cyclopropylamino or cyclopropylmethylamino; a C₄-C₆ cyclic amino group having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, such as 1-pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, piperidino or morpholino; a C₁-C₇ acylamino group such as trifluoroacetylamino group, formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino or valerylamino; a C₁-C₆ alkylsulfonylamino group such as methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino or butylsulfonylamino; a nitro group; and a cyano group).

In the formula (I), when G¹ represents a substituted or unsubstituted divalent aromatic hydrocarbon group having 6 to 14 carbon atoms, examples of the aromatic hydrocarbon group having 6 to 14 carbon atoms include a compound having at least one aromatic ring on its molecule, such as benzene, indene, indane, naphthalene, 1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthalene, azulene, acenaphthylene, acenaphthene, fluorene, phenanthrene or anthracene.

Examples of such preferred aromatic hydrocarbon group having 6 to 14 carbon atoms of G¹ include benzene, naphthalene and indane. Examples of more preferred aromatic hydrocarbon group having 6 to 14 carbon atoms of G¹ include benzene.

Exemplary substituents of the substituted aromatic hydrocarbon group having 6 to 14 carbon atoms of G¹ include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a hydroxy group, an optionally substituted C₁-C₇ alkoxy group, a C₆-C₁₀ aryloxy group, a C₇-C₉ aralkoxy group, a C₂-C₇-acyloxy group, an oxo group, a C₁-C₆ alkylsulfonyloxy group, an optionally substituted C₂-C₇ acyl group, a carboxyl group, a C₂-C₇ alkoxycarbonyl group, a carbamoyl group, an optionally substituted C₂-C₇ alkylcarbamoyl group, an amino group, an optionally substituted C₁-C₆ alkylamino group, an optionally substituted C₂-C₇ acylamino group, a C₂-C₈ alkoxycarbonylamino group, a C₁-C₆ alkylsulfonylamino group, a cyano group, a nitro group, a C₁-C₆ alkylthio group, a C₁-C₆ alkylsulfynyl group, a C₁-C₆ alkylsulfonyl group, a sulfamoyl group, a C₁-C₆ alkylaminosulfonyl group, a sulfo group, an optionally substituted alicyclic hydrocarbon group having 3 to 6 carbon atoms and an optionally substituted aliphatic hydrocarbon group having 1 to 6 carbon atoms.

Specific examples of the substituent of the substituted aromatic hydrocarbon group having 6 to 14 carbon atoms of G¹ include the same as those specifically exemplified as the substituents of the substituted alicyclic hydrocarbon group having 3 to 10 carbon atoms of G¹.

As the substituent of the substituted aromatic hydrocarbon group having 6 to 14 carbon atoms, the C₁-C₇ alkoxy group, the C₂-C₇ acyl group, the C₂-C₇ alkylcarbamoyl group, the C₁-C₆ alkylamino group, the C₂-C₇ acylamino group, the alicyclic hydrocarbon group having 3 to 6 carbon atoms or the aliphatic hydrocarbon group having 1 to 6 carbon atoms, may further be substituted with (one or more substituents selected from the group consisting of a fluorine atom; a chlorine atom; a bromine atom; an iodine atom; a hydroxy group; a C₁-C₆ alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy or cyclopropyloxy; a methoxymethyloxy group; a 2-methoxyethoxy group; a formyl group; a trifluoroacetyl group; a C₂-C₇ acyl group such as acetyl, propionyl, butyryl, isobutyryl, valeryl or isovaleryl; an oxo group; a carboxyl group; a C₂-C₇ alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl or t-butoxycarbonyl; a carbamoyl group; a C₂-C₇ alkylcarbamoyl group such as N-methylcarbamoyl, N,N-dimethylcarbamoyl, N-ethylcarbamoyl, N-ethyl-N-methylcarbamoyl, N,N-diethyl-carbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, N-cyclopropylcarbamoyl or N-cyclopropylmethylcarbamoyl; an amino group; a C₁-C₆ alkylamino group such as methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, N-ethylmethylamino, diethylamino, N-methylpropylamino, N-methylisopropylamino, cyclopropylamino or cyclopropylmethylamino; a C₄-C₆ cyclic amino group having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, such as 1-pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, piperidino or morpholino; a trifluoroacetylamino group; a C₁-C₇ acylamino group such as formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino or valerylamino; a C₁-C₆ alkylsulfonylamino group such as methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino or butylsulfonylamino; a nitro group; and a cyano group).

Preferred examples of the substituents of the substituted aromatic hydrocarbon group having 6 to 14 carbon atoms of G₁ include a fluorine atom; a chlorine atom; a bromine atom; a C₁-C₆ alkoxy group consisting of a straight or branched alkyl and oxy group, including methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy, t-pentyloxy and hexyloxy; a cyano group; a nitro group; a carboxyl group; a hydroxy group; an amino group; a C₁-C₆ mono or dialkylamino group consisting of a straight or branched alkyl and amino group, including methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, s-butylamino, t-butylamino, pentylamino, hexylamino, dimethylamino, N-ethylmethylamino, diethylamino, N-methylpropylamino, N-methylisopropylamino, N-methylbutyl-amino, N-methyl-t-butylamino, N-ethylisopropylamino, dipropylamino, diisopropylamino and ethylbutylamino; a carbamoyl group; an aminosulfonyl group; an alicyclic hydrocarbon group having 3 to 6 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; a C₂-C₇ acyl group including acetyl, propionyl, butyryl, isobutyryl, pivaroyl and hexanoyl; a C₁-C₆ alkylthio group including methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, s-butylthio, t-butylthio, pentylthio and hexylthio; a C₁-C₆ alkylsulfonyl group including methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, s-butylsulfonyl, t-butylsulfonyl, pentylsulfonyl and hexylsulfonyl; a C₂-C₇ alkoxycarbonyl group including acetoxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy, pivaloyloxy and hexanoyloxy; a C₂-C₇ acylamino group including acetylamino, propionylamino, butyrylamino, isobutyrylamino, valerylamino and hexanoylamino; trifluoromethyl group, trifluoromethoxy group, and an aliphatic hydrocarbon group having 1 to 6 carbon atoms which may contain a straight or branched unsaturated bond, including methyl, ethyl, vinyl, ethynyl, propyl, 1-propenyl, 2-propenyl, isopropyl, isopropenyl, 1-propynyl, 2-propynyl, butyl, isobutyl, s-butyl, t-butyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-butynyl, 2-butynyl, pentyl, isopentyl, neopentyl, t-pentyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, hexyl, 5-hexenyl, 4-methyl-3-pentenyl, isohexyl, 2-methylpentyl and 1-ethylbutyl.

Specifically, examples of more preferred substituents of the substituted aromatic hydrocarbon group having 6 to 14 carbon atoms include a fluorine atom, a chlorine atom, a bromine atom, C₁-C₆ alkoxy group, cyano group, a nitro group, a carboxyl group, a hydroxy group, an amino group, a C₁-C₆ mono or dialkylamino group, a carbamoyl group, an alicyclic hydrocarbon group having 3 to 6 carbon atoms, a C₂-C₇ acyl group, a C₁-C₆ alkylsulfonyl group, a C₂-C₇ alkoxycarboxyl group, trifluoromethyl group, trifluoromethoxy group, and a C₁-C₆ alkyl group including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, neopentyl, t-pentyl, hexyl, isohexyl, 2-methylpentyl and 1-ethylbutyl. Examples of particularly preferred substituents include a fluorine atom, a chlorine atom, a C₁-C₆ alkoxy group, a cyano group, a nitro group, a carboxyl group, a hydroxy group, an amino group, a C₁-C₆ mono or dialkylamino group, an alicyclic hydrocarbon group having 3 to 6 carbon atoms, a C₂-C₇ acyl group, a trifluoromethyl group, a trifluoromethoxy group and a C₁-C₆ alkyl group.

In the formula (I), when G¹ represents a divalent group derived from heterocyclic compounds having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on its substituted or unsubstituted ring, examples of such heterocyclic compounds include monocyclic, bicyclic or tricyclic heterocyclic compounds, such as furan, thiophene, pyrrole, pyrroline, pyrrolidine, oxazole, oxazolidine, isooxazole, isooxazolidine, thiazole, thiazolidine, isothiazole, isothiazolidine, furazan, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, triazole, thiadiazole, oxadiazole, tetrazole, pyran, tetrahydropyran, thiopyran, tetrahydrothiopyran, tetrahydrofuran, 1,3-dioxolane, 1,4-dioxane, pyridine, pyrazine, pyrimidine, pyridazine, benzofuran, dibenzofuran, 1,4-dioxacycloheptane, benzothiophene, indole, 1,2-methylene-dioxybenzene, benzimidazole, benzothiazole, benzooxazole, chroman, isochroman, quinoline, decahydrbquinoline, isoquinoline, phthalazine, cinnoline, 1,8-naphthylidine, 1,2,3,4-tetrahydroisoquinoline, quinazoline, quinoxaline, purine, pteridine, azetidine, morpholine, thiomorpholine, piperidine, homopiperidine, piperazine, homopiperazine, indoline, isoindoline, phenoxazine, phenazine, phenothiazine, pyrrolopyrimidine, pyrazolpyrimidine or quinuclidine.

Preferred examples of the heterocyclic compound having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring of G¹ include monocyclic or bicyclic C₂-C₉ aromatic heterocyclic compounds having 1 to 3 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, such as furan, pyrrole, thiophene, pyrazole, oxazole, thiazole, isooxazole, isothiazole, pyrazole, imidazole, pyridine, pyrimidine, pyrazine, pyridazine, benzothiophene, benzofuran, 1,2-methylenedioxybenzene, benzimidazole, indole, quinoline, isoquinoline, quinazoline, phthalazine, cinnoline or 1,8-naphthylidin; or monocyclic C₂-C₉ heterocyclic compounds having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, such as pyrrolidine, piperidine, morpholine, thiomorpholine, homopiperidine, homopiperazine, 1,2,3,6-tetrahydropyridine or piperazine.

The heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring of G¹ links to A² on a carbon atom or a nitrogen atom.

More preferred examples of the heterocyclic group linking to A² on a carbon atom include divalent groups derived from monocyclic or bicyclic C₃-C₉ aromatic heterocyclic compounds having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, such as furan, pyrrole, thiophene, pyrazole, oxazole, thiazole, isooxazole, isothiazole, pyrazole, imidazole, pyridine; pyrimidine, pyrazine, pyridazine, benzothiophene, benzofuran, 1,2-methylenedioxybenzene, benzimidazole, indole, quinoline, isoquinoline or quinazoline.

Meanwhile, preferred examples of the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, the heterocyclic group linking to A² on a nitrogen atom, include divalent groups derived from monocyclic or bicyclic C₂-C₉ heterocyclic compounds having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, such as pyrrolidine, piperidine, morpholine, thiomorpholine, homopiperidine, homopiperazine, 1,2,3,6-tetrahydropyridine or piperazine. More preferred examples of the monocyclic C₂-C₉ heterocyclic compounds having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, include piperidine, homopiperidine, morpholine, homopiperazine and piperazine.

Exemplary substituent of the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on its substituted ring of G¹, include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a hydroxy group, an optionally substituted C₁-C₇ alkoxy group, a C₆-C₁₀ aryloxy group, a C₇-C₉ aralkoxy group, a C₂-C₇ acyloxy group, an oxo group, a C₁-C₆ alkylsulfonyloxy group, an optionally substituted C₂-C₇ acyl group, a carboxyl group, a C₂-C₇ alkoxycarbonyl group, a carbamoyl group, an optionally substituted C₂-C₇ alkylcarbamoyl group, an amino group, an optionally substituted C₁-C₆ alkylamino group, an optionally substituted C₂-C₇ acylamino group, a C₂-C₈ alkoxycarbonylamino group, a C₁-C₆ alkylsulfonylamino group, a cyano group, a nitro group, a C₁-C₆ alkylthio group, a C₁-C₆ alkylsulfynyl group, a C₁-C₆ alkylsulfonyl group, a sulfamoyl group, a C₁-C₆ alkylaminosulfonyl group, a sulfo group, an optionally substituted alicyclic hydrocarbon group having 3 to 6 carbon atoms, and an optionally substituted aliphatic hydrocarbon group having 1 to 6 carbon atoms.

Specific examples of the substituent of the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on its substituted ring of G¹ include the same as those exemplified in the substituted alicyclic hydrocarbon group having 3 to 10 carbon atoms of G¹.

As the substituent of the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on its substituted ring of G¹, a C₁-C₇ alkoxy group, a C₂-C₇ acyl group, a C₂-C₇ alkylcarbamoyl group, a C₁-C₆ alkylamino group, a C₂-C₇ acylamino group, an alicyclic hydrocarbon group having 3 to 6 carbon atoms and aliphatic hydrocarbon group having 1 to 6 carbon atoms may further be substituted with (one or more substituents selected from the group consisting of a fluorine atom; a chlorine atom; a bromine atom; an iodine atom; a hydroxy group; a C₁-C₆ alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy or cyclopropyloxy; a methoxymethyloxy group; a 2-methoxyethoxy group; a formyl group; a trifluoroacetyl group; a C₂-C₇ acyl group such as acetyl, propionyl, butyryl, isobutyryl, valeryl or isovaleryl; an oxo group; a carboxyl group; a C₂-C₇ alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl or t-butoxycarbonyl; a carbamoyl group; a C₂-C₇ alkylcarbamoyl group such as N-methylcarbamoyl, N,N-dimethylcarbamoyl, N-ethylcarbamoyl, N-ethyl-N-methylcarbamoyl, N,N-diethylcarbamoyl, N-propylcarbamoyl, N-isopropyl-carbamoyl, N-butylcarbamoyl, N-cyclopropylcarbamoyl or N-cyclopropylmethylcarbamoyl; an amino group; a C₁-C₆ alkylamino group such as methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, N-ethylmethylamino, diethylamino, N-methylpropylamino, N-methylisopropylamino, cyclopropylamino or cyclopropylmethylamino; a C₄-C₆ cyclic amino group having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, such as 1-pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, piperidino or morpholino; a trifluoroacetylamino group; a C₁-C₇ acylamino group such as formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino or valerylamino; a C₁-C₆ alkylsulfonylamino group such as methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino or butylsulfonylamino; a nitro group; and a cyano group).

Preferred examples of the substituent of the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on its substituted ring of G¹, include a fluorine atom; a chlorine atom; a bromine atom; a C₁-C₆ alkoxy group consisting of a straight or branched alkyl and oxy group, including methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy, t-pentyloxy and hexyloxy; a cyano group; a nitro group; a carboxyl group; a hydroxy group; an amino group; a C₁-C₆ mono or dialkylamino group consisting of a straight or branched alkyl and amino group, including methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, s-butylamino, t-butylamino, pentylamino, hexylamino, dimethylamino, N-ethylmethylamino, diethylamino, N-methylpropylamino, N-methylisopropylamino, N-methylbutylamino, N-methyl-t-butylamino, N-ethylisopropylamino, dipropylamino, diisopropylamino and ethylbutylamino; a carbamoyl group; an aminosulfonyl group; an alicyclic hydrocarbon group having 3 to 6 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; a C₂-C₇ acyl group including acetyl, propionyl butyryl, isobutyryl, pivaroyl and hexanoyl; a C₁-C₆ alkylthio group including methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, s-butylthio, t-butylthio, pentylthio and hexylthio; a C₁-C₆ alkylsulfonyl group, including methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, s-butylsulfonyl, t-butylsulfonyl, pentylsulfonyl and hexylsulfonyl; a C₂-C₇ alkoxycarbonyl group including acetoxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy, pivaloyloxy and hexanoyloxy; a C₂-C₇ acylamino group including acetylamino, propionylamino, butyrylamino, isobutyrylamino, valerylamino and hexanoylamino; trifluoromethyl, trifluoromethoxy, and an aliphatic hydrocarbon group having 1 to 6 carbon atoms which may contain a straight or branched unsaturated bond, including methyl, ethyl, vinyl, ethynyl, propyl, 1-propenyl, 2-propenyl, isopropyl, isopropenyl, 1-propynyl, 2-propynyl, butyl, isobutyl, s-butyl, t-butyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-butynyl, 2-butynyl, pentyl, isopentyl, neopentyl, t-pentyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, hexyl, 5-hexenyl, 4-methyl-3-pentenyl, isohexyl, 2-methylpentyl and 1-ethylbutyl.

Specifically, more preferred examples of the substituent of the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on its substituted ring of G¹, include a fluorine atom, a chlorine atom, a bromine atom, C₁-C₆ alkoxy group, cyano group, a nitro group, a carboxyl group, a hydroxy group, an amino group, a C₁-C₆ mono or dialkylamino group, a carbamoyl group, an alicyclic hydrocarbon group having 3 to 6 carbon atoms, a C₂-C₇ acyl group, a C₁-C₆ alkylsulfonyl group, a C₂-C₇ alkoxycarboxyl group, a trifluoromethyl group, a trifluoromethoxy group, and a C₁-C₆ alkyl group including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, neopentyl, t-pentyl, hexyl, isohexyl, 2-methylpentyl and 1-ethylbutyl. Examples of particularly preferred substituents include a fluorine atom, a chlorine atom, a C₁-C₆ alkoxy group, a cyano group, a nitro group, a carboxyl group, a hydroxy group, an amino group, a C₁-C₆ mono or dialkylamino group, an alicyclic hydrocarbon group having 3 to 6 carbon atoms, a C₂-C₇ acyl group, a trifluoromethyl group, a trifluoromethoxy group and a C₁-C₆ alkyl group.

In the present invention, G¹ in the formula (I) is preferably a single bond, a monocyclic aliphatic hydrocarbon group having 3 to 6 carbon atoms, a phenylene group, a monocyclic or bicyclic aromatic hydrocarbon group having 3 to 9 carbon atoms having 1 or 2 atoms selected from among a group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom, in the ring, or a monocyclic heterocyclic group having 2 to 9 carbon atoms having 1 or 2 atoms selected from among a group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom, in the ring.

In the formula (I), G² represents a hydrogen atom, a substituted or unsubstituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms, a substituted or unsubstituted alicyclic hydrocarbon group having 3 to 10 carbon atoms, a substituted or unsubstituted aromatic hydrocarbon group having 6 to 14 carbon atoms, or a substituted or unsubstituted heterocyclic group having 1 to 4 atoms selected from among a group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom, in the ring.

In formula (I), when G² represents a substituted or unsubstituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms, examples of such a acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms of G² include an alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, neopentyl, t-pentyl, 2-methylpentyl, 4-methylpentyl, 1-ethylbutyl, hexyl, heptyl, 2-methylhexyl, 5-methylhexyl, 1,1-dimethylpentyl, 6-methylheptyl, octyl, nonyl or decyl, an alkenyl group such as vinyl, 1-methylvinyl, 1-ethylvinyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 2-methyl-1-butenyl, 1,3-butadienyl, 1-pentenyl, 2-pentenyl, 4-methyl-1-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1,5-hexadienyl, 2-heptenyl, 2-octenyl, 2-nonenyl or 2-decenyl, or an alkynyl group such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 3-methyl-1-butynyl, 3,3-dimethyl-1-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 1-methyl-3-pentynyl, 1-methyl-3-hexynyl, 2-heptynyl, 2-octynyl, 2-nonynyl or 2-decynyl.

Specifically, more preferred examples of such aliphatic hydrocarbon group having 1 to 10 carbon atoms include a straight or branched C₁-C₆ alkyl group which may contain a unsaturated bond such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, vinyl, 1-prophenyl, 1-butenyl, ethynyl or 1-propynyl. Particularly preferred examples of such a acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms include a straight or branched C₁-C₆ alkyl group such as methyl, ethyl, propyl, isopropyl, butyl or hexyl.

Exemplary substituents of the substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms of G² include: a fluorine atom; a chlorine atom; a bromine atom; an iodine atom; a hydroxy group; a C₁-C₇ alkoxy group consisting of a straight or branched alkyl group, cycloalkyl group and oxy group, including methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy, t-pentyloxy, hexyloxy, isohexyloxy, 2-methylpentyloxy, 1-ethylbutoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cyclopropylmethyloxy, cyclopropylethyloxy, cyclopentyl methyloxy and cyclohexylmethyloxy; an alkyldioxy group having 1 to 4 carbon atoms such as ethylene dioxy; a C₆-C₁₀ aryloxy group, including phenoxy, 1-naphthoxy and 2-naphthoxy; a C₇-C₉ aralkoxy group, including benzyloxy, α-phenethyloxy, β-phenethyloxy and phenylpropyloxy; a C₂-C₇ acyloxy group including acetoxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy, pivaloyloxy and hexanoyloxy; an oxo group; a C₁-C₆ alkylsulfonyloxy group consisting of a straight or branched alkyl and sulfonyloxy, including oxo, methylsulfonyloxy, ethylsulfonyloxy, propylsulfonyloxy, butylsulfonyloxy and t-butylsulfonyloxy; a C₂-C₇ acyl group, including acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaroyl and hexanoyl; a carboxyl group; a C₂-C₇ alkoxycarbonyl group consisting of a straight or branched alkyl and oxycarbonyl group, including methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, s-butoxycarbonyl and t-butoxycarbonyl; a carbamoyl group; a C₂-C₇ alkylcarbamoyl group consisting of a straight or branched alkyl, cycloalkyl and carbamoyl group, including N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, N-isobutylcarbamoyl, N-s-butylcarbamoyl, N-t-butylcarbamoyl, N-pentylcarbamoyl, N-cyclopropylcarbamoyl, N-cyclobutylcarbamoyl, N-cyclopentylcarbamoyl, N-cyclohexylcarbamoyl, N-cycloheptylcarbamoyl, N-cyclopropylmethylcarbamoyl, N,N-dimethylcarbamoyl, N-ethyl-N-methylcarbamoyl, N,N-diethylcarbamoyl and N,N-dipropylcarbamoyl; an amino group; a C₁-C₆ alkylamino group consisting of a straight or branched alkyl, cycloalkyl and amino group, including methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, s-butylamino, t-butylamino, pentylamino, hexylamino, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, cyclopropylmethylamino, dimethylamino, N-ethylmethylamino, diethylamino, N-methylpropylamino, N-methylisopropylamino, N-methylbutylamino, N-methyl-t-butylamino, N-methylisopropylamino, dipropylamino, diisopropylamino and ethylbutylamino; a C₂-C₇ acylamino group including acetylamino, propionylamino, butyrylamino, isobutyrylamino, valerylamino and hexanoylamino; a C₂-C₈ alkoxycarbonylamino group, including methoxycarbonylamino, ethoxycarbonylamino and t-butoxy-carbonylamino; a C₁-C₆ alkylsulfonylamino group including methylsulfonylamino, ethylsulfonylamino, butylsulfonylamino and t-butylsulfonylamino; a cyano group; a nitro group; a C₁-C₆ alkylthio group including methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, s-butylthio, t-butylthio, pentylthio and hexylthio; a C₁-C₆ alkylsulfynyl group consisting of a straight or branched alkyl, cycloalkyl and sulfynyl group, including methylsulfynyl, ethylsulfynyl, propylsulfynyl, isopropylsulfynyl, butylsulfynyl, isobutylsulfynyl, s-butylsulfynyl, t-butylsulfynyl, pentylsulfynyl and cyclopentylsulfynyl; a C₁-C₆ alkylsulfonyl group consisting of a straight or branched alkyl, cycloalkyl and sulfonyl group, including methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, s-butylsulfonyl, t-butylsulfonyl, pentylsulfonyl, hexylsulfonyl, cyclopentylsulfonyl and cyclohexylsulfonyl; a sulfo group; a sulfamoyl group; a C₁-C₆ aminosulfonyl group consisting of a straight or branched alkyl, cycloalkyl and aminosulfonyl group, including methylaminosulfonyl, ethylaminosulfonyl, propylaminosulfonyl, isopropylaminosulfonyl, butylaminosulfonyl, isobutyl-aminosulfonyl, s-butylaminosulfonyl, pentylaminosulfonyl, dimethylaminosulfonyl, N-ethyl-N-methylaminosulfonyl, diethylaminosulfonyl, dipropylaminosulfonyl, cyclopropylaminosulfonyl, cyclopentylaminosulfonyl, cyclohexylaminosulfonyl and cyclopropylmethylaminosulfonyl; an alicyclic hydrocarbon group having 3 to 6 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; and an aliphatic hydrocarbon group having 1 to 6 carbon atoms which may contain a straight or branched unsaturated bond, including methyl, ethyl, vinyl, ethynyl, propyl, 1-propenyl, 2-propenyl, isopropyl, isopropenyl, 1-propynyl, 2-propynyl, butyl, isobutyl, s-butyl, t-butyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-butynyl, 2-butynyl, pentyl, isopentyl, neopentyl, t-pentyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, hexyl, 5-hexenyl, 4-methyl-3-pentenyl, isohexyl, 2-methylpentyl and 1-ethylbutyl; an aromatic hydrocarbon group having 6 to 14 carbon atoms which is a monovalent group derived from monocyclic, bicyclic or tricyclic aromatic hydrocarbon group, including benzene, naphthalene, indene, indane, 1,2,3,4-tetrahydronaphthalene, and fluorene; and a monovalent group derived from monocyclic, bicyclic or tricyclic heterocyclic compound, including furan, thiophene, pyrrole, pyrroline, pyrrolidine, oxazole, oxazolidine, isooxazole, isooxazolidine, thiazole, thiazolidine, isothiazole, isothiazolidine, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, triazole, thiadiazole, oxadiazole, tetrazole, pyran, tetrahydropyran, thiopyran, tetrahydrothiopyran, pyridine, pyrazine, pyrimidine, pyridazine, benzofuran, dibenzofuran, benzothiophene, indole, benzimidazole, benzothiazole, benzooxazole, chroman, isochroman, quinoline, decahydroquinoline, isoquinoline, quinazolin, quinoxaline, purine, pteridine, azetidine, morpholine, thiomorpholine, piperidine, homopiperidine, piperazine, homopiperazine, indoline, isoindoline, phenoxazine, phenazine, phenothiazine and quinuclidine, the heterocyclic compound (having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring).

Preferred examples of the substituent of the substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms as G² include a fluorine atom, a hydroxy group, an optionally substituted C₁-C₇ alkoxy group, an oxo group, an optionally substituted C₂-C₇ acyl group, a carboxyl group, a C₂-C₇ alkoxycarbonyl group, a carbamoyl group, an optionally substituted C₂-C₇ alkylcarbamoyl group, an amino group, an optionally substituted C₁-C₆ alkylamino group, an optionally substituted C₂-C₇ acylamino group, a C₁-C₆ alkylsulfonylamino group, a cyano group, a C₁-C₆ alkylsulfonyl group, a sulfamoyl group, an optionally substituted aromatic hydrocarbon group having 6 to 14 carbon atoms and an optionally substituted heterocyclic group (having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring).

More preferred exemplary substituents of the substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms as G² include a fluorine atom, a hydroxy group, an optionally substituted C₁-C₇ alkoxy group, a carboxyl group, an amino group, an optionally substituted C₁-C₆ alkylamino group, a cyano group, a benzyl group, and an optionally substituted heterocyclic group (having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring).

As the substituent of the substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms as G², the heterocyclic group (having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring), links to the aliphatic hydrocarbon group having 1 to 10 carbon atoms as G² on a carbon atom or a nitrogen atom.

Preferred examples of the heterocyclic group (having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring), links to the aliphatic hydrocarbon group having 1 to 10 carbon atoms as G² on a carbon atom, include a monovalent group derived from a monocyclic or bicyclic C₃-C₉ aromatic heterocyclic compound, including furan, pyrrole, thiophene, pyrazole, oxazole, thiazole, isooxazole, isothiazole, pyrazole, imidazole, pyridine, pyrimidine, pyrazine, pyridazine, benzothiophene, benzofuran, 1,2-methylenedioxybenzene, benzimidazole, indole, quinoline, isoquinoline and quinazolin, the monovalent group having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring.

Meanwhile, preferred examples of the heterocyclic group (having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring), links to the acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms as G² on a nitrogen atom, include a monovalent group derived from a monocyclic C₂-C₉ heterocyclic compound, including pyrrolidine, piperidine, morpholine, thiomorpholine, homopiperidine, homopiperazine, 1,2,3,6-tetrahydropyridine and piperazine, the monovalent group having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring.

As the substituent of the substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms as G², a C₁-C₇ alkoxy group, a C₂-C₇ acyl group, C₂-C₇ alkylcarbamoyl, a C₁-C₆ alkylamino group, a C₂-C₇ acylamino group, an alicyclic hydrocarbon group having 3 to 6 carbon atoms, an aliphatic hydrocarbon group having 1 to 6 carbon atoms, aromatic hydrocarbon group having 6 to 14 carbon atoms, and heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, may further be substituted with (one or more substituents selected from the group consisting of: a fluorine atom; a chlorine atom; a bromine atom; an iodine atom; a hydroxy group; a C₁-C₆ alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy or cyclopropyloxy; a methoxymethyloxy group; a 2-methoxyethoxy group; a formyl group; a trifluoroacetyl group; a C₂-C₇ acyl group such as acetyl, propionyl, butyryl, isobutyryl, valeryl or isovaleryl; an oxo group; a carboxyl group; a C₂-C₇ alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl or t-butoxycarbonyl; a carbamoyl group; a C₂-C₇ alkylcarbamoyl group such as N-methylcarbamoyl, N,N-dimethylcarbamoyl, N-ethylcarbamoyl, N-ethyl-N-methylcarbamoyl, N,N-diethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, N-cyclopropyl-carbamoyl or N-cyclopropylmethylcarbamoyl; an amino group; a C₁-C₆ alkylamino group such as methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, N-ethylmethylamino, diethylamino, N-methylpropylamino, N-methylisopropylamino, cyclopropylamino or cyclopropylmethylamino; a C₄-C₆ cyclic amino group having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, such as 1-pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, piperidino or morpholino; a trifluoroacetylamino group; a C₁-C₇ acylamino group such as formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino or valerylamino; a C₁-C₆ alkylsulfonylamino group such as methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino or butylsulfonylamino; a nitro group; a cyano group; a C₁-C₆ alkyl group including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, and t-butyl; a trifluoromethyl group; and a trifluoromethoxy group).

In the formula (I), when G² represents a substituted or unsubstituted alicyclic hydrocarbon group having 3 to 10 carbon atoms, examples of the alicyclic hydrocarbon group having 3 to 10 carbon atoms of G² include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, and cyclooctyl group. Preferred examples of the alicyclic hydrocarbon group having 3 to 10 carbon atoms of G² include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3-cyclopentenyl, 4-cyclopentenyl, 1-cyclohexenyl, 3-cyclohexenyl, 4-cyclohexenyl, and 1-cycloheptenyl.

Exemplary substituents of the substituted alicyclic hydrocarbon group having 3 to 10 carbon atoms of G² include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a hydroxy group, an optionally substituted C₁-C₇ alkoxy group, C₁-C₄ alkylenedioxy group, a C₆-C₁₀ aryloxy group, a C₇-C₉ aralkoxy group, a C₂-C₇ acyloxy group, an oxo group, a C₁-C₆ alkylsulfonyloxy group, an optionally substituted C₂-C₇ acyl group, a carboxyl group, a C₂-C₇ alkoxycarbonyl group, a carbamoyl group, an optionally substituted C₂-C₇ alkylcarbamoyl group, an amino group, an optionally substituted C₁-C₆ alkylamino group, an optionally substituted C₂-C₇ acylamino group, a C₂-C₈ alkoxycarbonylamino group, a C₁-C₆ alkylsulfonylamino group, a cyano group, a nitro group, a C₁-C₆ alkylthio group, a C₁-C₆ alkylsulfynyl group, a C₁-C₆ alkylsulfonyl group, a sulfamoyl group, a C₁-C₆ alkylaminosulfonyl group, a sulfo group, an optionally substituted alicyclic hydrocarbon group having 3 to 6 carbon atoms, and an optionally substituted aliphatic hydrocarbon group having 1 to 6 carbon atoms, an optionally substituted aromatic hydrocarbon group having 6 to 14 carbon atoms.

Specific examples of the substituent of the substituted alicyclic hydrocarbon group having 3 to 10 carbon atoms of G² include the same as those exemplified in the substituted aliphatic hydrocarbon group having 1 to 10 carbon atoms of G².

As the substituent of the substituted alicyclic hydrocarbon group having 3 to 10 carbon atoms of G², a C₁-C₇ alkoxy group, a C₂-C₇ acyl group, a C₂-C₇ alkylcarbamoyl group, a C₁-C₆ alkylamino group, a C₂-C₇ acylamino group, an alicyclic hydrocarbon group having 3 to 6 carbon atoms, an aliphatic hydrocarbon group having 1 to 6 carbon atoms, and an aromatic hydrocarbon group having 6 to 14 carbon atoms, may further be substituted with (one or more substituents selected from the group consisting of: a fluorine atom; a chlorine atom; a bromine atom; an iodine atom; a hydroxy group; a C₁-C₆ alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy or cyclopropyloxy; a methoxymethyloxy group; a 2-methoxyethoxy group; a formyl group; a trifluoroacetyl group; a C₂-C₇ acyl group such as acetyl, propionyl, butyryl, isobutyryl, valeryl or isovaleryl; an oxo group; a carboxyl group; a C₂-C₇ alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl or t-butoxycarbonyl; a carbamoyl group; a C₂-C₇ alkylcarbamoyl group such as N-methylcarbamoyl, N,N-dimethylcarbamoyl, N-ethylcarbamoyl, N-ethyl-N-methylcarbamoyl, N,N-diethyl-carbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, N-cyclopropylcarbamoyl or N-cyclopropylmethylcarbamoyl; an amino group; a C₁-C₆ alkylamino group such as methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, N-ethylmethylamino, diethylamino, N-methylpropylamino, N-methylisopropylamino, cyclopropylamino or cyclopropylmethylamino; a C₄-C₆ cyclic amino group having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, such as 1-pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, piperidino or morpholino; a trifluoroacetylamino group; a C₁-C₇ acylamino group such as formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino or valerylamino, a C₁-C₆ alkylsulfonylamino group such as methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino or butylsulfonylamino; a nitro group; a cyano group; a C₁-C₆ alkyl group including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, and t-butyl; a trifluoromethyl group; and a trifluoromethoxy group).

In the formula (I), when G² represents a substituted or unsubstituted aromatic hydrocarbon group having 6 to 14 carbon atoms, examples of the aromatic hydrocarbon group having 6 to 14 carbon atoms include a monovalent group having at least one aromatic ring on its molecule, such as benzene, indene, indane, naphthalene, 1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthalene, azulene, acenaphthylene, acenaphthene, fluorene, phenanthrene or anthracene. Examples of such preferred aromatic hydrocarbon group having 6 to 14 carbon atoms of G² include a phenyl group.

Exemplary substituents of the aromatic hydrocarbon group having 6 to 14 carbon atoms of G² include at least one substituent selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a hydroxy group, an optionally substituted C₁-C₇ alkoxy group, a C₁-C₄ alkylenedioxy group, a C₆-C₁₀ aryloxy group, a C₇-C₉ aralkoxy group, a C₂-C₇ acyloxy group, an oxo group, a C₁-C₆ alkylsulfonyloxy group, an optionally substituted C₂-C₇ acyl group, a carboxyl group, a C₂-C₇ alkoxycarbonyl group, a carbamoyl group, an optionally substituted C₂-C₇ alkylcarbamoyl group, an amino group, an optionally substituted C₁-C₆ alkylamino group, an optionally substituted C₂-C₇ acylamino group, a C₂-C₈ alkoxycarbonylamino group, a C₁-C₆ alkylsulfonylamino group, a cyano group, a nitro group, a C₁-C₆ alkylthio group, a C₁-C₆ alkylsulfynyl group, a C₁-C₆ alkylsulfonyl group, a sulfamoyl group, a C₁-C₆ alkylaminosulfonyl group, a sulfo group, an optionally substituted alicyclic hydrocarbon group having 3 to 6 carbon atoms, an optionally substituted aliphatic hydrocarbon group having 1 to 6 carbon atoms, and an optionally substituted aromatic hydrocarbon group having 6 to 14 carbon atoms.

Specific examples of the substituent of the substituted C₆-C₁₄ aromatic hydrocarbon group of G² include the same as those exemplified in the substituent of the substituted aliphatic hydrocarbon group having 1 to 10 carbon atoms of G².

As the substituents of the aromatic hydrocarbon group having 6 to 14 carbon atoms of G², a C₁-C₇ alkoxy group, a C₂-C₇ acyl group, a C₂-C₇ alkylcarbamoyl group, a C₁-C₆ alkylamino group, a C₂-C₇ acylamino group, an alicyclic hydrocarbon group having 3 to 6 carbon atoms, an aliphatic hydrocarbon group having 1 to 6 carbon atoms, and an aromatic hydrocarbon group having 6 to 14 carbon atoms, may further be substituted with (one or more substituents selected from the group consisting of: a fluorine atom; a chlorine atom; a bromine atom; an iodine atom; a hydroxy group; a C₁-C₆ alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy or cyclopropyloxy; a methoxymethyloxy group; a 2-methoxyethoxy group; a formyl group; a trifluoroacetyl group; a C₂-C₇ acyl group such as acetyl, propionyl, butyryl, isobutyryl, valeryl or isovaleryl; an oxo group; a carboxyl group; a C₂-C₇ alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl or t-butoxycarbonyl; a carbamoyl group; a C₂-C₇ alkylcarbamoyl group such as N-methylcarbamoyl, N,N-dimethylcarbamoyl, N-ethylcarbamoyl, N-ethyl-N-methylcarbamoyl, N,N-diethyl-carbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, N-cyclopropylcarbamoyl or N-cyclopropylmethylcarbamoyl; an amino group; a C₁-C₆ alkylamino group such as methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, N-ethylmethylamino, diethylamino, N-methylpropylamino, N-methylisopropylamino, cyclopropylamino or cyclopropylmethylamino; a C₄-C₆ cyclic amino group having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, such as 1-pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, piperidino or morpholino; a trifluoroacetylamino group; a C₁-C₇ acylamino group such as formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino or valerylamino; a C₁-C₆ alkylsulfonylamino group such as methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino or butylsulfonylamino; a nitro group; a cyano group; a C₁-C₆ alkyl group including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, and t-butyl; a trifluoromethyl group; and a trifluoromethoxy group).

In the formula (I), when G² represents a heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on its substituted or unsubstituted ring, examples of such heterocyclic group include a monovalent group derived from monocyclic, bicyclic or tricyclic compounds, including furan, thiophene, pyrrole, pyrroline, pyrrolidine, oxazole, oxazolidine, isooxazole, isooxazolidine, thiazole, thiazolidine, isothiazole, isothiazolidine, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, triazole, thiadiazole, oxadiazole, tetrazole, pyran, tetrahydropyran, thiopyran, tetrahydrothiopyran, pyridine, pyrazine, pyrimidine, pyridazine, benzofuran, dibenzofuran, benzothiophene, indole, 1,2-methylene-dioxybenzene, benzimidazole, benzothiazole, benzooxazole, chroman, isochroman, quinoline, decahydroquinoline, isoquinoline, quinazolin, quinoxaline, purine, pteridine, azetidine, morpholine, thiomorpholine, piperidine, homopiperidine, piperazine, homopiperazine, indoline, isoindoline, phenoxazine, phenazine, phenothiazine and quinuclidine.

Preferred examples of the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring of G² include 2-pyridyl, 3-pyridyl, 4-pyridyl, piperidino, 2-piperizyl, 3-piperizyl, 4-piperizyl, morpholino, 1-homopiperidinyl, 1-pyrrolidinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-pyrazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 4-isooxazolyl, 2-pyrimidinyl, 4-pyrimidinyl, 2-pyrazinyl, 4-triazolyl, 5-tetrazolyl, 1-piperazinyl, 4-tetrahydropyranyl, 2-1,3,4-oxadiazolyl, 4-1,2,3-thiadiazolyl, 2-benzofuranyl, 2-benzothiazolyl, 2-indolyl, 3-indolyl, 5-benzoimidazolyl and 2-1,2,3,4-tetrahydroisoquinolinyl group.

The heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring of G², links to A⁴ on a carbon atom or a nitrogen atom.

More preferred examples of the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring of G², the heterocyclic group linking to A⁴ on a carbon atom, include a monovalent group derived from a monocyclic or bicyclic C₃-C₉ aromatic heterocyclic compound having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, such as furan, pyrrole, thiophene, pyrazole, oxazole, thiazole, isooxazole, isothiazole, pyrazole, imidazole, pyridine, pyrimidine, pyrazine, pyridazine, benzothiophene, benzofuran, 1,2-methylenedioxy-benzene, benzimidazole, indole, quinoline, isoquinoline or quinazolin.

Meanwhile, preferred examples of the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring of G², the heterocyclic group linking to A⁴ on a nitrogen atom, include a monovalent group derived from a monocyclic C₂-C₉ heterocyclic compound having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, such as pyrrolidine, piperidine, morpholine, thiomorpholine, homopiperidine, homopiperazine, 1,2,3,6-tetrahydropyridine or piperazine.

More preferred examples of the heterocyclic group as G² include a monovalent group derived from a monocyclic C₄-C₆ heterocyclic compound having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, such as piperidine, homopiperidine, morpholine, homopiperazine, or piperazine.

Exemplary substituents of the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on its substituted ring of G² include at least one substituent selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a hydroxy group, an optionally substituted C₁-C₇ alkoxy group, a C₁-C₄ alkylenedioxy group, a C₆-C₁₀ aryloxy group, a C₇-C₉ aralkoxy group, a C₂-C₇ acyloxy group, an oxo group, a C₁-C₆ alkylsulfonyloxy group, an optionally substituted C₂-C₇ acyl group, a carboxyl group, a C₂-C₇ alkoxycarbonyl group, a carbamoyl group, an optionally substituted C₂-C₇ alkylcarbamoyl group, an amino group, an optionally substituted C₁-C₆ alkylamino group, an optionally substituted C₂-C₇ acylamino group, a C₂-C₈ alkoxycarbonylamino group, a C₁-C₆ alkylsulfonylamino group, a cyano group, a nitro group, a C₁-C₆ alkylthio group, a C₁-C₆ alkylsulfynyl group, a C₁-C₆ alkylsulfonyl group, a sulfamoyl group, a C₁-C₆ alkylaminosulfonyl group, a sulfo group, an optionally substituted alicyclic hydrocarbon group having 3 to 6 carbon atoms, an optionally substituted aliphatic hydrocarbon group having 1 to 6 carbon atoms, and an optionally substituted aromatic hydrocarbon group having 6 to 14 carbon atoms and.

The substituents of the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring of G² are as defined above for the substituent of the substituted aliphatic hydrocarbon group having 1 to 10 carbon atoms of G².

As the substituent of the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on its substituted ring of G², a C₁-C₇ alkoxy group, a C₂-C₇ acyl group, a C₂-C₇ alkylcarbamoyl group, a C₁-C₆ alkylamino group, a C₂-C₇ acylamino group, an alicyclic hydrocarbon group having 3 to 6 carbon atoms, an aliphatic hydrocarbon group having 1 to 6 carbon atoms, and an aromatic hydrocarbon group having 6 to 14 carbon atoms, may further be substituted with (one or more substituents selected from the group consisting of: a fluorine atom; a chlorine atom; a bromine atom; an iodine atom; a hydroxy group; a C₁-C₆ alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy or cyclopropyloxy; a methoxymethyloxy group; a 2-methoxyethoxy group; a formyl group; a trifluoroacetyl group; a C₂-C₇ acyl group such as acetyl, propionyl, butyryl, isobutyryl, valeryl or isovaleryl; an oxo group; a carboxyl group; a C₂-C₇ alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl or t-butoxycarbonyl; a carbamoyl group; a C₂-C₇ alkylcarbamoyl group such as N-methylcarbamoyl, N,N-dimethylcarbamoyl, N-ethylcarbamoyl, N-ethyl-N-methylcarbamoyl, N,N-diethylcarbamoyl, N-propylcarbamoyl, N-isopropyl-carbamoyl, N-butylcarbamoyl, N-cyclopropylcarbamoyl or N-cyclopropylmethylcarbamoyl; an amino group; a C₁-C₆ alkylamino group such as methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, N-ethylmethylamino, diethylamino, N-methylpropylamino, N-methylisopropylamino, cyclopropylamino or cyclopropylmethylamino; a C₄-C₆ cyclic amino group having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, such as 1-pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, piperidino or morpholino; a trifluoroacetylamino group; a C₁-C₇ acylamino group such as formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino or valerylamino; a C₁-C₆ alkylsulfonylamino group such as methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino or butylsulfonylamino; a nitro group; a cyano group; a C₁-C₆ alkyl group including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, and t-butyl; a trifluoromethyl group; and a trifluoromethoxy group).

In the present description, when G¹, G², or the substituent of G² represents a substituted or unsubstituted aromatic hydrocarbon group, a substituted or unsubstituted alicyclic hydrocarbon group, or a substituted or unsubstituted heterocyclic group, the aromatic hydrocarbon group, alicyclic hydrocarbon group, or heterocyclic group is preferably selected from the group consisting of cyclopropane, cyclopentane, cyclohexane, cyclohexene, cycloheptane, *nolvolnane, adamantine, benzene, naphthalene, indane, indoles, 1,3-benzodioxol, benzoimidazol, benzotriazol, pyrazol, imidazol, pyrazoron, thiazol, tetrazol, 1,2,4-oxadiazol, isooxazol, furan, thiophene, pyridine, pyradine, pyrrole, morpholine, benzofuran, benzothiophene, piperazine, pyrrolidine, homopiperizine, tetrahydroisoquinoline, pyrimidine, and quinazoline.

Next, an explanation will be given of preferred combinations of A¹, A², G¹, A³, A⁴ and G² in the formula (I).

When both of A¹ and A³ represent aliphatic hydrocarbon group, at least one of A² and G¹ is not a single bond.

The preferred combinations of A¹, A², G¹, A³, A⁴ and G², and preferred combinations including also substituents of them if they have substituents are basically preferably combinations of those preferably selected from among A¹, A², G¹, A³, A⁴ and G², and substituents of them. Then, more preferred combinations are combinations of more preferred elements.

In the formula (I), A¹ represents a divalent acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms, particularly preferably represents —(CH₂)₂— or —(CH₂)₃—.

More preferably, A² simultaneously represents those other than the single bond, and especially preferably A² represents —C(═O)—, —C(═O)—O—, —C(═O)—NH—, —C(═O)—NMe-, —NH—, —NH—C(═O)—, —NH—C(═O)—O—, —NH—C(═O)—NH—, —NH—C(═O)—NMe-, or —NH—C(═S)—. Specifically preferably A² represents —C(═O)—NH—, —NH—, —NH—C(═O)—, —NH—C(═O)—O—, or —NH—C(═O)—NH—.

Meanwhile, where A¹ represents a single bond, preferably also A represents a single bond.

Preferred combinations of G¹, A³, A⁴ and G² of G¹-G² portion include combinations of 1 to 10 of the following table.

Combi-
nation	G1	A3	A4	G2
1	Group other	Single bond	Single bond	Hydrogen
	than single			atom
	bond
2	Single bond	Group other than	Single bond	Hydrogen
		single bond		atom
3	Group other	Single bond	Single bond	Group other
	than single			than a
	bond			hydrogen
				atom
4	Single bond	Group other than	Single bond	Group other
		single bond		than a
				hydrogen
				atom
5	Group other	Single bond	Group other	Group other
	than single		than single	than a
	bond		bond	hydrogen
				atom
6	Single bond	Group other than	Group other	Group other
		single bond	than single	than a
			bond	hydrogen
				atom
7	Group other	Group other than	Single bond	Group other
	than single	single bond		than a
	bond			hydrogen
				atom
8	Group other	Group other than	Group other	Group other
	than single	single bond	than single	than a
	bond		bond	hydrogen
				atom
9	Group other	Group other than	Group other	Hydrogen
	than single	single bond	than single	atom
	bond		bond
10	Single bond	Single bond	Single bond	Hydrogen
				atom

In the table, in combinations of numbers 4 to 7, A³ represents an alkylene group having 1 to 3 carbon atoms.

Also, in the combination of number 5, A⁴ preferably represents —C(═O)—, —C(═O)—NH—, —O—, or —NH—C(═O)—.

Also, in the combination of number 8, A⁴ preferably represents —O—.

Further, combinations of the following a) to f) are preferable.

a) A¹ represents —(CH₂)₂— or —(CH₂)₃—, A² represents —NH—(C═O)— or —NH—(C═O)—NH—, G¹ represents a single bond, and A³ represents a divalent acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms.

b) A¹ represents —(CH₂)₂— or —(CH₂)₃—, A² represents —NH—(C═O)—, —NH—(C═O)—NH—, —NH—, or —C—(═O)—NH—, and G¹ represents a group other than the single bond.

c) A¹ represents a divalent acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms, specifically —(CH₂)₂— or —(CH₂)₃—, A² represents a single bond, and G¹ represents an optionally substituted heterocyclic group (note, where a heterocyclic group of G¹ is 5 or 6 membered monocyclic ring, the 5 or 6 membered monocyclic heterocyclic group of G¹ is substituted, or A³-G² portion represents those other than the hydrogen atom).

d) A¹ represents a divalent acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms, specifically —(CH₂)₂— or —(CH₂)₃—, A² represents those other than a single bond, and G¹ represents an optionally substituted aromatic hydrocarbon group, an optionally substituted alicyclic hydrocarbon group having 7 to 10 carbon atoms, or an optionally substituted heterocyclic group (note, where the aromatic hydrocarbon group of G¹ is a phenyl group, or where the heterocyclic group of G¹ is 5 or 6 membered monocyclic ring, the phenyl group or 5 or 6 membered monocyclic heterocyclic group of G¹ is substituted, or A³-G² portion represents those other than the hydrogen atom).

e) A¹ represents a divalent acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms, specifically —(CH₂)₂— or —(CH₂)₃—, A² represents those other than a single bond, G¹ and A⁴ represent the single bond, A³ represents an optionally substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms, G² represents an optionally substituted alicyclic hydrocarbon group having 5 to 10 carbon atoms, an optionally substituted aromatic hydrocarbon group, or optionally substituted heterocyclic group.

f) A¹ represents a divalent acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms, specifically —(CH₂)₂— or —(CH₂)₃—, A² represents those other than a single bond, G¹ represents the single bond, A³ represents an optionally substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms, and A⁴ represents —C(═O)—, —C(═O)—NR¹²¹—, —C(═S)—NR¹²²—, —C(═NR¹²³), —O—C(═O)—, —NR¹²⁵—C(═O)—, —NR¹²⁶—S(═O)₂—, —NR¹²⁷—C(═O)—O—, —NR¹²⁸—C(═O)—NR¹²⁹—, —NR¹³⁰—C(═S)—, —NR¹³¹—C(═S)—NR¹³²—, —S—, —S(═O)—, —S(═O)₂—, —S(═O)₂—NR¹³³— or —S(═O)₂—O—.

In the cases of d) to f), A² preferably represents —C(═O)—, —C(═O)—O—, —C(═O)—NH—, —C(═O)—NMe-, —NH—, —NH—C(═O)—, —NH—C(═O)—O—, —NH—C(═O)—NH—, —NH—C(═O)—NMe-, or —NH—C(═S)—, especially preferably represents —C(═O)—NH—, —NH—, —NH—C(═O)—, —NH—C(═O)—O—, or —NH—C(═O)—NH—.

In the formula (I), A⁵ represents a single bond or represents a group that links R² with a carbon atom of a pyrrole ring to which A⁵ is bonded, in the form of R²—NR²⁰¹-pyrrole ring (R²⁰¹ represents a hydrogen atom or a acyclic aliphatic hydrocarbon group having 1 to 4 carbon atoms), when A⁵ bonds R² and a carbon atom of a pyrrole ring to which A⁵ is bonded, in the form of R²—NR²⁰¹-pyrrole ring, examples of the acyclic aliphatic hydrocarbon group having 1 to 4 carbon atoms of R²⁰¹ are the same as those exemplified as R¹⁰¹ of A² described above. Preferred examples of R¹⁰² include a hydrogen atom, methyl, ethyl or propyl group, and specifically preferably hydrogen atom and methyl group.

Preferred examples of A⁵ include a single bond, —NH—, and N(CH₃)—, and specifically preferably single bond.

In the formula (I), R² represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, an optionally substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms, an optionally substituted alicyclic hydrocarbon group having 3 to 8 carbon atoms, an optionally substituted aromatic hydrocarbon group having 6 to 14 carbon atoms, or an optionally substituted heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring.

R² in the formula (I) is preferably a chlorine atom or a bromine atom among a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

In the formula (I), when R² represents an optionally substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms, examples of acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms of R² are the same as those exemplified of the acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms of G². Preferred examples of the acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms of R² include methyl, ethyl, isopropyl, butyl, isobutyl, t-butyl, t-pentyl, vinyl, 2-propenyl, 2-methyl-1-propenyl, and 2-propenyl.

Substituents for the substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms of R² include at least one substituent selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a hydroxy group, an optionally substituted C₁-C₇ alkoxy group, a C₆-C₁₀ aryloxy group, a C₇-C₉ aralkoxy group, a C₂-C₇ acyloxy group, an oxo group, a C₁-C₆ alkylsulfonyloxy group, an optionally substituted C₂-C₇ acyl group, a carboxyl group, a C₂-C₇ alkoxycarbonyl group, a carbamoyl group, an optionally substituted C₂-C₇ alkylcarbamoyl group, an amino group, an optionally substituted C₁-C₆ alkylamino group, an optionally substituted C₂-C₇ acylamino group, a C₂-C₈ alkoxycarbonylamino group, a C₁-C₆ alkylsulfonylamino group, a cyano group, a nitro group, a C₁-C₆ alkylthio group, a C₁-C₆ alkylsulfynyl group, a C₁-C₆ alkylsulfonyl group, a sulfamoyl group, a C₁-C₆ alkylaminosulfonyl group, a sulfo group, an optionally substituted alicyclic hydrocarbon group having 1 to 6 carbon atoms, an optionally substituted acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms, an optionally substituted aromatic hydrocarbon group having 6 to 14 carbon atoms, and an optionally substituted heterocyclic group (having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring).

Specific examples of the substituent of the substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms of R² include the same as those exemplified as the substituents of the substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms of G².

As the substituent of substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms as R², a C₁-C₇ alkoxy group, a C₂-C₇ acyl group, C₂-C₇ alkylcarbamoyl group, a C₁-C₆ alkylamino group, a C₂-C₇-acylamino group, an alicyclic hydrocarbon group having 3 to 6 carbon atoms, a acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms, aromatic hydrocarbon group having 6 to 14 carbon atoms, and heterocyclic group (having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring), may further be substituted with (one or more substituents selected from the group consisting of: a fluorine atom; a chlorine atom; a bromine atom; an iodine atom; a hydroxy group; a C₁-C₆ alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy or cyclopropyloxy; a methoxymethyloxy group; a 2-methoxyethoxy group; a formyl group; a trifluoroacetyl group; a C₂-C₇ acyl group such as acetyl, propionyl, butyryl, isobutyryl, valeryl or isovaleryl; an oxo group; a carboxyl group; a C₂-C₇ alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl or t-butoxycarbonyl; a carbamoyl group; a C₂-C₇ alkylcarbamoyl group such as N-methylcarbamoyl, N,N-dimethylcarbamoyl, N-ethylcarbamoyl, N-ethyl-N-methylcarbamoyl, N,N-diethyl-carbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, N-cyclopropylcarbamoyl or N-cyclopropyl-methylcarbamoyl; an amino group; a C₁-C₆ alkylamino group such as methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, N-ethylmethylamino, diethylamino, N-methylpropylamino, N-methylisopropylamino, cyclopropylamino or cyclopropylmethylamino; a C₄-C₆ cyclic amino group having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, such as 1-pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, piperidino or morpholino; a trifluoroacetylamino group; a C₁-C₇ acylamino group such as formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino or valerylamino; a C₁-C₆ alkylsulfonylamino group such as methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino or butylsulfonylamino; a nitro group; a cyano group; a C₁-C₆ alkyl group including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, and t-butyl; a trifluoromethyl group; and a trifluoromethoxy group).

In the formula (I), when R² represents a substituted or unsubstituted alicyclic hydrocarbon group having 3 to 8 carbon atoms, examples of the alicyclic hydrocarbon group having 3 to 8 carbon atoms of R² the same as defined above for the substituents of the substituted alicyclic hydrocarbon group having 3 to 8 carbon atoms of G². Preferred examples of the alicyclic hydrocarbon group having 3 to 8 carbon atoms of R² include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Among them, the cyclopropyl group is preferred.

Exemplary substituents of the substituted alicyclic hydrocarbon group having 3 to 8 carbon atoms of R² include at least one substituent selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a hydroxy group, an optionally substituted C₁-C₇ alkoxy group, a C₆-C₁₀ aryloxy group, a C₇-C₉ aralkoxy group, a C₂-C₇ acyloxy group, an oxo group, a C₁-C₆ alkylsulfonyloxy group, an optionally substituted C₂-C₇ acyl group, a carboxyl group, a C₂-C₇ alkoxycarbonyl group, a carbamoyl group, an optionally substituted C₂-C₇ alkylcarbamoyl group, an amino group, an optionally substituted C₁-C₆ alkylamino group, an optionally substituted C₂-C₇ acylamino group, a C₂-C₈ alkoxycarbonylamino group, a C₁-C₆ alkylsulfonylamino group, a cyano group, a nitro group, a C₁-C₆ alkylthio group, a C₁-C₆ alkylsulfynyl group, a C₁-C₆ alkylsulfonyl group, a sulfamoyl group, a C₁-C₆ alkylaminosulfonyl group, a sulfo group, an optionally substituted alicyclic hydrocarbon group having 3 to 6 carbon atoms, an optionally substituted aliphatic hydrocarbon group having 1 to 6 carbon atoms, an optionally substituted aromatic hydrocarbon group having 6 to 14 carbon atoms, and an optionally substituted heterocyclic group (having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring).

Specific examples of the substituent of the substituted alicyclic hydrocarbon group having 3 to 8 carbon atoms of R² include the same as those exemplified in the substituted alicyclic hydrocarbon group having 1 to 10 carbon atoms of G².

As the substituent of the substituted alicyclic hydrocarbon group having 3 to 8 carbon atoms of R², a C₁-C₇ alkoxy group, a C₂-C₇ acyl group, a C₂-C₇ alkylcarbamoyl group, a C₁-C₆ alkylamino group, a C₂-C₇ acylamino group, an alicyclic hydrocarbon group having 3 to 6 carbon atoms, an aliphatic hydrocarbon group having 1 to 6 carbon atoms, an aromatic hydrocarbon group having 6 to 14 carbon atoms and a heterocyclic group (having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring), may further be substituted with (one or more substituents selected from the group consisting of: a fluorine atom; a chlorine atom; a bromine atom; an iodine atom; a hydroxy group; a C₁-C₆ alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy or cyclopropyloxy; a methoxymethyloxy group; a 2-methoxyethoxy group; a formyl group; a trifluoroacetyl group; a C₂-C₇ acyl group such as acetyl, propionyl, butyryl, isobutyryl, valeryl or isovaleryl; an oxo group; a carboxyl group; a C₂-C₇ alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl or t-butoxycarbonyl; a carbamoyl group; a C₂-C₇ alkylcarbamoyl group such as N-methylcarbamoyl, N,N-dimethylcarbamoyl, N-ethylcarbamoyl, N-ethyl-N-methylcarbamoyl, N,N-diethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, N-cyclopropyl-carbamoyl or N-cyclopropylmethylcarbamoyl; an amino group; a C₁-C₆ alkylamino group such as methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, N-ethylmethyl-amino, diethylamino, N-methylpropylamino, N-methylisopropyl-amino, cyclopropylamino or cyclopropylmethylamino; a C₄-C₆ cyclic amino group having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, such as 1-pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, piperidino or morpholino; a trifluoroacetylamino group; a C₁-C₇ acylamino group such as formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino or valerylamino; a C₁-C₆ alkylsulfonylamino group such as methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino or butylsulfonylamino; a nitro group; a cyano group; a C₁-C₆ alkyl group including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, and t-butyl; a trifluoromethyl group, and a trifluoromethoxy group).

In the formula (I), when R² is a substituted or unsubstituted aromatic hydrocarbon group having 6 to 14 carbon atoms, examples of the aromatic hydrocarbon group having 6 to 14 carbon atoms of R² include the same as those exemplified in the aromatic hydrocarbon group having 6 to 14 carbon atoms of G². Examples of such preferred aromatic hydrocarbon group having 6 to 14 carbon atoms of R² include a phenyl group.

Exemplary substituents of the substituted aromatic hydrocarbon group having 6 to 14 carbon atoms include at least one substituent selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a hydroxy group, a C₁-C₆ alkyl group, an optionally substituted C₁-C₇ alkoxy group, a C₆-C₁₀ aryloxy group, a C₇-C₉ aralkoxy group, a C₂-C₇ acyloxy group, an oxo group, a C₁-C₆ alkylsulfonyloxy group, an optionally substituted C₂-C₇ acyl group, a carboxyl group, a C₂-C₇ alkoxycarbonyl group, a carbamoyl group, an optionally substituted C₂-C₇ alkylcarbamoyl group, an amino group, an optionally substituted C₁-C₆ alkylamino group, an optionally substituted C₂-C₇ acylamino group, a C₂-C₈ alkoxycarbonylamino group, a C₁-C₆ alkylsulfonylamino group, a cyano group, a nitro group, a C₁-C₆ alkylthio group, a C₁-C₆ alkylsulfynyl group, a C₁-C₆ alkylsulfonyl group, a sulfamoyl group, a C₁-C₆ alkylaminosulfonyl group, a sulfo group, an optionally substituted alicyclic hydrocarbon group having 3 to 6 carbon atoms, an optionally substituted aliphatic hydrocarbon group having 1 to 6 carbon atoms, an optionally substituted aromatic hydrocarbon group having 6 to 14 carbon atoms, and an optionally substituted heterocyclic group (having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring).

Specific examples of the substituent of the substituted aromatic hydrocarbon group having 6 to 14 carbon atoms R² include the same as those exemplified for the substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms of G².

As the substituent of the aromatic hydrocarbon group having 6 to 14 carbon atoms of R², a C₁-C₇ alkoxy group, a C₂-C₇ acyl group, a C₂-C₇ alkylcarbamoyl group, a C₁-C₆ alkylamino group, a C₂-C₇ acylamino group, an alicyclic hydrocarbon group having 3 to 6 carbon atoms, an aliphatic hydrocarbon group having 1 to 6 carbon atoms, an aromatic hydrocarbon group having 6 to 14 carbon atoms and heterocyclic group (having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring), may further be substituted with (one or more substituents selected from the group consisting of: a fluorine atom; a chlorine atom; a bromine atom; an iodine atom; a hydroxy group; a C₁-C₆ alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy or cyclopropyloxy; a methoxymethyloxy group; a 2-methoxyethoxy group; a formyl group; a trifluoroacetyl group, a C₂-C₇ acyl group such as acetyl, propionyl, butyryl, isobutyryl, valeryl or isovaleryl; an oxo group; a carboxyl group; a C₂-C₇ alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl or t-butoxycarbonyl; a carbamoyl group; a C₂-C₇ alkylcarbamoyl group such as N-methylcarbamoyl, N,N-dimethylcarbamoyl, N-ethylcarbamoyl, N-ethyl-N-methylcarbamoyl, N,N-diethyl-carbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, N-cyclopropylcarbamoyl or N-cyclopropyl-methylcarbamoyl; an amino group; a C₁-C₆ alkylamino group such as methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, N-ethylmethylamino, diethylamino, N-methylpropylamino, N-methylisopropylamino, cyclopropylamino or cyclopropylmethylamino; a C₄-C₆ cyclic amino group having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, such as 1-pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, piperidino or morpholino; a trifluoroacetylamino group; a C₁-C₇ acylamino group such as formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino or valerylamino; a C₁-C₆ alkylsulfonylamino group such as methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino or butylsulfonylamino; a nitro group; a cyano group; a C₁-C₆ alkyl group including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, and t-butyl; a trifluoromethyl group, and a trifluoromethoxy group).

In the formula (I), when R² represents a heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on its substituted or unsubstituted ring of R², examples of heterocyclic group of R² include the same as those exemplified for the heterocyclic group of G² The heterocyclic group of R² links to A⁵ on a carbon atom or a nitrogen atom.

Examples of preferred heterocyclic group linking to A⁵ on a carbon atom include a monocyclic or cyclic C₃-C₉ aromatic heterocyclic group having 1 to 3 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, such as furyl, thienyl, pyrrolyl, pyrazolyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzofuranyl, indolyl, benzothienyl, quinolyl, isoquinolyl, quinazolyl, benzoimidazolyl or benzooxazolyl. More preferred example of the heterocyclic group include a monocyclic or bicyclic C₃-C₉ aromatic heterocyclic compound having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, such as 2-furyl, 2-thienyl, 2-pyrrolyl, 2-imidazolyl, 5-imidazolyl, 4-pyrazolyl, 2-oxazolyl, 5-oxazolyl, 5-isooxazolyl, 2-thiazolyl, 5-thiazolyl, 5-isothiazolyl, 3-isothiazolyl, 2-pyridyl, 2-pyrimidinyl, 2-benzofuranyl or 2-benzothiophenyl group. Further, particularly preferable examples of the heterocyclic group include a monocyclic C₃-C₅ aromatic heterocyclic group having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, and most preferably, 2-furyl, 2-thienyl, 2-pyrrolyl, 2-pyridyl or 4-pyrazolyl.

Meanwhile, preferred examples of the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, links to A⁵ on a nitrogen atom, include 1-pyrazolyl, 1-imidazolyl, 1-pyrrolidinyl, piperidino, morpholino, 1-homopiperidinyl and 1-piperazinyl. When the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on a ring of R², links to A⁵ on a nitrogen atom, A⁵ represents a single bond.

Exemplary substituents of the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on the substituted ring of R² include at least one substituent selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a hydroxy group, an optionally substituted C₁-C₇ alkoxy group, a C₆-C₁₀ aryloxy group, a C₇-C₉ aralkoxy group, a C₂-C₇ acyloxy group, an oxo group, a C₁-C₆ alkylsulfonyloxy group, an optionally substituted C₂-C₇ acyl group, a carboxyl group, a C₂-C₇ alkoxycarbonyl group, a carbamoyl group, an optionally substituted C₂-C₇ alkylcarbamoyl group, an amino group, an optionally substituted C₁-C₆ alkylamino group, an optionally substituted C₂-C₇ acylamino group, a C₂-C₈ alkoxycarbonylamino group, a C₁-C₆ alkylsulfonylamino group, a cyano group, a nitro group, a C₁-C₆ alkylthio group, a C₁-C₆ alkylsulfynyl group, a C₁-C₆ alkylsulfonyl group, a sulfamoyl group, a C₁-C₆ alkylaminosulfonyl group, a sulfo group, an optionally substituted alicyclic hydrocarbon group having 3 to 6 carbon atoms, an optionally substituted aliphatic hydrocarbon group having 1 to 6 carbon atoms, an optionally substituted aromatic hydrocarbon group having 6 to 14 carbon atoms, and an optionally substituted heterocyclic group (having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring).

Specific examples of the substituent of the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on its substituted ring of R² include the same as those exemplified as the substituents of the substituted aliphatic hydrocarbon group having 1 to 10 carbon atoms of G².

As the substituent of the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on its substituted ring of R², a C₁-C₇ alkoxy group, a C₂-C₇ acyl group, a C₂-C₇ alkylcarbamoyl group, a C₁-C₆ alkylamino group, a C₂-C₇ acylamino group, an alicyclic hydrocarbon group having 3 to 6 carbon atoms, aliphatic hydrocarbon group having 1 to 6 carbon atoms, an aromatic hydrocarbon group having 6 to 14 carbon atoms, and a heterocyclic group (having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring) may further be substituted with (one or more substituents selected from the group consisting of: a fluorine atom; a chlorine atom; a bromine atom; an iodine atom; a hydroxy group; a C₁-C₆ alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy or cyclopropyloxy; a methoxymethyloxy group; a 2-methoxyethoxy group; a formyl group; a trifluoroacetyl group; a C₂-C₇ acyl group such as acetyl, propionyl, butyryl, isobutyryl, valeryl or isovaleryl; an oxo group; a carboxyl group; a C₂-C₇ alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl or t-butoxycarbonyl; a carbamoyl group; a C₂-C₇ alkylcarbamoyl group such as N-methylcarbamoyl, N,N-dimethylcarbamoyl, N-ethylcarbamoyl, N-ethyl-N-methylcarbamoyl, N,N-diethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, N-cyclopropylcarbamoyl or N-cyclopropylmethylcarbamoyl; an amino group; a C₁-C₆ alkylamino group such as methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, N-ethylmethylamino, diethylamino, N-methylpropylamino, N-methylisopropylamino, cyclopropylamino or cyclopropylmethylamino; a C₄-C₆ cyclic amino group having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, such as 1-pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, piperidino or morpholino; a trifluoroacetylamino group; a C₁-C₇ acylamino group such as formylamino, acetylamino, propionylamino, butyrylamino, isbbutyrylamino or valerylamino; a C₁-C₆-alkylsulfonylamino group such as methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino or butylsulfonylamino; a nitro group; a cyano group; a C₁-C₆ alkyl group including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, and t-butyl; a trifluoromethyl group; and a trifluoromethoxy group).

Among exemplary substituents of the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on its substituted ring of R², preferred examples of the substituent include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a hydroxy group, a cyano group, a nitro group, an amino group, a C₁-C₆ mono or dialkylamino group consisting of a straight or branched alkyl group and an amino group, such as substituted or unsubstituted methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, s-butylamino, t-butylamino, pentylamino, hexylamino, dimethylamino, N-ethylmethylamino, diethylamino, N-methylpropylamino, N-methylisopropylamino, N-methylbutylamino, N-methyl-t-butylamino, N-ethylisopropylamino, dipropylamino, diisopropylamino and ethylbutylamino, a carboxyl group, an optionally substituted saturated a C₁-C₆ alkyl group including a substituted or unsubstituted methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, neopentyl, t-pentyl, hexyl, isohexyl, 2-methylpentyl and 1-ethylbutyl, an alicyclic hydrocarbon group having 3 to 6 carbon atoms including cyclopropyl, cyclobutyl, cyclo pentyl and cyclohexyl, an optionally substituted C₁-C₆ alkoxy group consisting of a straight or branched alkyl group and an oxy group, including a substituted or unsubstituted methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy, t-pentyloxy and hexyloxy, a C₂-C₇ acyl group, including a substituted or unsubstituted acetyl, propionyl, butyryl, isobutyryl, pivaroyl and hexanoyl, a C₁-C₆ alkylthio group, including methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, s-butylthio, t-butylthio, pentylthio and hexylthio, trifluoromethyl group, trifluoromethoxy group, a C₂-C₇ acylamino group, including substituted or unsubstituted acetylamino, propionylamino, butyrylamino, isobutyrylamino, valerylamino and hexanoylamino, and a C₂-C₇ alkylcarbamoyl group consisting of a straight or branched alkyl group and a carbamoyl group, including a substituted or unsubstituted N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, N-isobutylcarbamoyl, N-s-butylcarbamoyl, N-t-butylcarbamoyl, N-pentylcarbamoyl, N,N-dimethylcarbamoyl, N-ethyl-N-methylcarbamoyl and N,N-diethylcarbamoyl.

More preferred examples of the substituent of the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on its substituted ring as R², include one or more of a fluorine atom, a chlorine atom, a bromine atom, an acyl group having 2 to 4 carbon atoms, a hydroxy group, a carboxyl group, an alkoxycarbonyl group, a substituted or unsubstituted C₁-C₆ alkyl group, a hydroxy group, and a substituted or unsubstituted C₁-C₆ alkoxy group.

Here, an explanation will be given of preferred combinations of R² and A⁵ of the formula (I).

In combinations of R² and A⁵ of the formula (I) in the present invention, when R² is a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, A⁵ represents a single bond.

Preferred examples of the combinations of R² and A⁵ of the formula (I) in the present invention include those representing an aliphatic hydrocarbon group having 1 to 10 carbon atoms wherein A⁵ represents a single bond, and R² may be substituted, an optionally substituted alicyclic hydrocarbon group having 3 to 8 carbon atoms, an optionally substituted aromatic hydrocarbon group having 6 to 14 carbon atoms, or an optionally substituted heterocyclic group. Specific preferred combinations are combinations representing an aliphatic hydrocarbon group having 1 to 10 carbon atoms wherein A⁵ represents a single bond, and R² may be substituted, an optionally substituted alicyclic hydrocarbon group having 3 to 8 carbon atoms, an optionally substituted phenyl group, or an optionally substituted heterocyclic group having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring. Among them, cases where R² represents a cyclopropyl group, a cyclobutyl group, a cyclopropylmethyl group, a methyl group, an ethyl group, a vinyl group, an isopropyl group, an isobutyl group or 2-methyl-1-propenyl group are preferred.

Also, combinations of A⁵ and R² in which A⁵ represents a single bond and R² represents a thienyl group, a pyridyl group, a furyl group, a pyrazolyl group or a phenyl group are preferable, wherein the thienyl group, the pyridyl group, the furyl group, the pyrazolyl group or the phenyl group may be further substituted by one or more of a C₁-C₄ alkyl group, a C₁-C₄ alkoxy group, a C₂-C₄ acyl group, a hydroxy group, a carboxyl group, an alkoxycarbonyl group, a fluorine atom or a chlorine atom.

Also a combination wherein A⁵ is NR²⁰¹-, and R² represents a hydrogen atom or an optionally substituted aliphatic hydrocarbon group having 1 to 10 carbon atoms is preferred.

In the formula (I), A⁶ is a single bond, a group that links a carbon atom of a pyrrole ring in which R³ and A⁶ are linked to each other in the form of R³—NR³⁰¹-pyrrole ring, R³—C(═O)-pyrrole ring, R³—NR³⁰²—C(═O)-pyrrole ring, R³—NR³⁰³—C(═S)-pyrrole ring, R³—NR³⁰⁴—C(═O)—NR³⁰⁵-pyrrole ring, R³—C(═O)—NR³⁰⁶-pyrrole ring, R³—NR³⁰⁷—CH═N-pyrrole ring, R³—O—C(═O)-pyrrole ring, R³—C(═O)—O-pyrrole ring, R³—O-pyrrole ring, R³—S-pyrrole ring, R³—S(═O)-pyrrole ring, R³—S(═O)₂-pyrrole ring, R³—CR³⁰⁸═CR³⁰⁹-pyrrole ring, R³—C≡C-pyrrole ring, or R³—S(═O)₂—C≡C-pyrrole ring (R³⁰¹ through R³⁰⁹ are each independently a hydrogen atom or a C₁-C₄ aliphatic hydrocarbon group.)

When R³-A⁶- and a carbon atom of a pyrrole ring are linked to each other in the form of R³—NR³⁰¹-pyrrole ring, examples of such C₁-C₄ aliphatic hydrocarbon group of R³⁰¹ include the same as those selected as the examples of R¹⁰¹ in A². Examples of such preferred R³⁰¹ include a hydrogen atom, methyl, and ethyl group. Particularly, a hydrogen atom is preferred.

When R³-A⁶- and a carbon atom of a pyrrole ring are linked to each other in the form of R³—NR³⁰²—C(═O)-pyrrole ring, examples of such C₁-C₄ aliphatic hydrocarbon group of R³⁰² include the same as those selected as the examples of R¹ in A². Examples of such preferred R³⁰² include a hydrogen atom, methyl, and ethyl group. Particularly, a hydrogen atom is preferred.

When R³-A⁶- and a carbon atom of a pyrrole ring are linked to each other in the form of R³—NR³⁰³—C(═S)-pyrrole ring, examples of such C₁-C₄ aliphatic hydrocarbon group of R³⁰³ include the same as those selected as the examples of R¹⁰¹ in A². Examples of such preferred R³⁰³ include a hydrogen atom, methyl, and ethyl group. Particularly, a hydrogen atom is preferred.

When R³-A⁶- and a carbon atom of a pyrrole ring are linked to each other in the form of R³—NR³⁰⁴——C(═O)—NR³⁰⁵-pyrrole ring, examples of such C₁-C₄ aliphatic hydrocarbon group of R³⁰⁴ and R³⁰⁵ include the same as those selected as the examples of R¹⁰¹ in A². Examples of such preferred R³⁰⁴ and R³⁰⁵ include a hydrogen atom, methyl, and ethyl group. Particularly, a hydrogen atom is preferred.

When R³-A⁶- and a carbon atom of a pyrrole ring are linked to each other in the form of R³—C(═O)—NR³⁰⁶-pyrrole ring, examples of such C₁-C₄ aliphatic hydrocarbon group of R³⁰⁶ include the same as those selected as the examples of R¹⁰¹ in A². Examples of such preferred R³⁰⁶ include a hydrogen atom, methyl, and ethyl group. Particularly, a hydrogen atom is preferred.

When R³-A⁶- and a carbon atom of a pyrrole ring are linked to each other in the form of R³—NR³⁰⁷—CH═N-pyrrole ring, examples of such C₁-C₄ aliphatic hydrocarbon group of R³⁰⁷ include the same as those selected as the examples of R¹⁰¹ in A². Examples of such preferred R³⁰⁷ include a hydrogen atom, methyl, and ethyl group. Particularly, methyl group is preferred.

When R³-A⁶- and a carbon atom of a pyrrole ring are linked to each other in the form of R³—CR³⁰⁸═CR³⁰⁹-pyrrole ring, examples of such C₁-C₄ aliphatic hydrocarbon group of R³⁰⁸ and R³⁰⁸ include the same as those selected as the examples of R¹⁰¹ in A².

In the formula (I), R³ represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a nitro group, a substituted or unsubstituted saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms, a substituted or unsubstituted alicyclic hydrocarbon group having 3 to 8 carbon atoms, a substituted or unsubstituted aromatic hydrocarbon group having 6 to 14 carbon atoms, or a heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom.

As R³ in the formula (I), among a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom, a chlorine atom, a bromine atom, and an iodine atom are preferred.

In the formula (I), when R³ represents a substituted or unsubstituted acyclic saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms, examples of the acyclic saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms of R³ include an alkyl group, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, neopentyl, t-pentyl, 2-methylpentyl, 4-methylpentyl, 1-ethylbutyl, hexyl, heptyl, 2-methylhexyl, 5-methylhexyl, 1,1-dimethylpentyl, 6-methylheptyl, octyl, nonyl, and decyl. Preferred examples of the acyclic saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms of R³ include methyl, ethyl, isopropyl, butyl, t-butyl, and t-pentyl group.

As the substituent of the substituted acyclic saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms of R³ include at least one substituent selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a hydroxy group, an optionally substituted C₁-C₇ alkoxy group, a C₆-C₁₀ aryloxy group, a C₇-C₉ aralkoxy group, a C₂-C₇ acyloxy group, an oxo group, an optionally substituted C₂-C₇ acyl group, a carboxyl group, a C₂-C₇ alkoxycarbonyl group, a carbamoyl group, an optionally substituted C₂-C₇ alkylcarbamoyl group, an amino group, an optionally substituted C₁-C₆ alkylamino group, an optionally substituted C₂-C₇ acylamino group, a C₂-C₈ alkoxycarbonylamino group, a C₁-C₆ alkylsulfonylamino group, a cyano group, a nitro group, a C₁-C₆ alkylthio group, a C₁-C₆ alkylsulfynyl group, an optionally substituted alicyclic hydrocarbon group having 3 to 6 carbon atoms, an optionally substituted aliphatic hydrocarbon group having 1 to 6 carbon atoms, an optionally substituted aromatic hydrocarbon group having 6 to 14 carbon atoms and an optionally substituted heterocyclic group (having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring).

Specific examples of the substituent of the substituted acyclic saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms of R³ include the same as those exemplified in the substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms of G².

As the substituent of the substituted acyclic saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms of R³, a C₁-C₇ alkoxy group, a C₂-C₇ acyl group, a C₂-C₇ alkylcarbamoyl group, a C₁-C₆ alkylamino group, a C₂-C₇ acylamino group, an alicyclic hydrocarbon group having 3 to 6 carbon atoms, an aliphatic hydrocarbon group having 1 to 6 carbon atoms, an aromatic hydrocarbon group having 6 to 14 carbon atoms and a heterocyclic group (having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring), may further be substituted with (one or more substituents selected from the group consisting of: a fluorine atom; a chlorine atom; a bromine atom; an iodine atom; a hydroxy group; a C₁-C₆ alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy or cyclopropyloxy; a methoxymethyloxy group; a 2-methoxyethoxy group; a formyl group; a trifluoroacetyl group; a C₂-C₇ acyl group such as acetyl, propionyl, butyryl, isobutyryl, valeryl or isovaleryl; an oxo group; a carboxyl group; a C₂-C₇ alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl or t-butoxycarbonyl; a carbamoyl group; a C₂-C₇ alkylcarbamoyl group such as N-methylcarbamoyl, N,N-dimethylcarbamoyl, N-ethylcarbamoyl, N-ethyl-N-methylcarbamoyl, N,N-diethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, N-cyclopropyl-carbamoyl or N-cyclopropylmethylcarbamoyl; an amino group; a C₁-C₆ alkylamino group such as methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, N-ethylmethyl-amino, diethylamino, N-methylpropylamino, N-methylisopropyl-amino, cyclopropylamino or cyclopropylmethylamino; a C₄-C₆ cyclic amino group having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, such as 1-pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, piperidino or morpholino; a trifluoroacetylamino group; a C₁-C₇ acylamino group such as formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino or valerylamino, a C₁-C₆ alkylsulfonylamino group such as methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino or butylsulfonylamino; a nitro group; a cyano group; a C₁-C₆ alkyl group including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, and t-butyl; a trifluoromethyl group; and a trifluoromethoxy group).

In the formula (I), when R³ represents a substituted or unsubstituted alicyclic hydrocarbon group having 3 to 8 carbon atoms, examples of the alicyclic hydrocarbon group having 3 to 8 carbon atoms of R² include the same as those exemplified in the alicyclic hydrocarbon group having 3 to 10 carbon atoms of G². Preferred examples of the alicyclic hydrocarbon group having 3 to 8 carbon atoms of R² include cyclopropyl, cyclobutyl and cyclopentyl, cyclohexyl.

Exemplary substituents of the substituted alicyclic hydrocarbon group having 3 to 8 carbon atoms of R³ include at least one substituent selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a hydroxy group, an optionally substituted C₁-C₇ alkoxy group, a C₆-C₁₀ aryloxy group, a C₇-C₉ aralkoxy group, a C₂-C₇ acyloxy group, an optionally substituted C₂-C₇ acyl group, a carboxyl group, a C₂-C₇ alkoxycarbonyl group, a carbamoyl group, an optionally substituted C₂-C₇ alkylcarbamoyl group, an amino group, an optionally substituted C₁-C₆ alkylamino group, an optionally substituted C₂-C₇ acylamino group, a C₂-C₈ alkoxycarbonylamino group, a cyano group, a nitro group, an optionally substituted alicyclic hydrocarbon group having 3 to 6 carbon atoms, an optionally substituted aliphatic hydrocarbon group having 1 to 6 carbon atoms, an optionally substituted aromatic hydrocarbon group having 6 to 14 carbon atoms and an optionally substituted heterocyclic group (having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring).

Specific examples of the substituent of the substituted alicyclic hydrocarbon group having 3 to 8 carbon atoms of R³ include the same as those exemplified as the substituents of the substituted the substituents of the substituted aliphatic hydrocarbon group having 1 to 10 carbon atoms of G².

As the substituent of the substituted alicyclic hydrocarbon group having 3 to 8 carbon atoms of R³, a C₁-C₇ alkoxy group, a C₂-C₇ acyl group, a C₂-C₇ alkylcarbamoyl group, a C₁-C₆ alkylamino group, a C₂-C₇ acylamino, an alicyclic hydrocarbon group having 3 to 6 carbon atoms, an aliphatic hydrocarbon group having 1 to 6 carbon atoms, an aromatic hydrocarbon group having 6 to 14 carbon atoms, and a heterocyclic group (having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring), may further be substituted with (one or more substituents selected from the group consisting of: a fluorine atom; a chlorine atom; a bromine atom; an iodine atom; a hydroxy group; a C₁-C₆ alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy or cyclopropyloxy; a methoxymethyloxy group; a 2-methoxyethoxy group; a formyl group; a trifluoroacetyl group; a C₂-C₇ acyl group such as acetyl, propionyl, butyryl, isobutyryl, valeryl or isovaleryl; an oxo group; a carboxyl group; a C₂-C₇ alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl or t-butoxycarbonyl; a carbamoyl group; a C₂-C₇ alkylcarbamoyl group such as N-methylcarbamoyl, N,N-dimethylcarbamoyl, N-ethylcarbamoyl, N-ethyl-N-methylcarbamoyl, N,N-diethyl-carbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, N-cyclopropylcarbamoyl or N-cyclopropyl-methylcarbamoyl; an amino group; a C₁-C₆ alkylamino group such as methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, N-ethylmethylamino, diethylamino, N-methylpropylamino, N-methylisopropylamino, cyclopropylamino or cyclopropylmethylamino; a C₄-C₆ Cyclic amino group having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, such as 1-pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, piperidino or morpholino; a trifluoroacetylamino group; a C₁-C₇ acylamino group such as formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino or valerylamino; a C₁-C₆ alkylsulfonylamino group such as methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino or butylsulfonylamino; a nitro group; a cyano group; a C₁-C₆ alkyl group including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, and t-butyl; a trifluoromethyl group; and a trifluoromethoxy group).

In the formula (I), when R³ represents a substituted or unsubstituted aromatic hydrocarbon group having 6 to 14 carbon atoms, examples of the aromatic hydrocarbon group having 6 to 14 carbon atoms of R³ include the same as those exemplified in the aromatic hydrocarbon group having 6 to 14 carbon atoms of G². Preferred examples of the aromatic hydrocarbon group having 6 to 14 carbon atoms of R³ include a phenyl group.

Exemplary substituents of the substituted aromatic hydrocarbon group having 6 to 14 carbon atoms of R³ include at least one substituent selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a hydroxy group, an optionally substituted C₁-C₇ alkoxy group, a C₆-C₁₀ aryloxy group, a C₇-C₉ aralkoxy group, a C₂-C₇ acyloxy group, an oxo group, a C₁-C₆ alkylsulfonyloxy group, an optionally substituted C₂-C₇ acyl group, a carboxyl group, a C₂-C₇ alkoxycarbonyl group, a carbamoyl group, an optionally substituted C₂-C₇ alkylcarbamoyl group, an amino group, an optionally substituted C₁-C₆ alkylamino group, an optionally substituted C₂-C₇ acylamino group, a C₂-C₈ alkoxycarbonylamino group, a C₁-C₆ alkylsulfonylamino group, a cyano group, a nitro group, a C₁-C₆ alkylthio group, a C₁-C₆ alkylsulfynyl group, a C₁-C₆ alkylsulfonyl group, a sulfamoyl group, a C₁-C₆ alkylaminosulfonyl group, a sulfo group, an optionally substituted alicyclic hydrocarbon group having 3 to 6 carbon atoms, an optionally substituted aliphatic hydrocarbon group having 1 to 6 carbon atoms, an optionally substituted aromatic hydrocarbon group having 6 to 14 carbon atoms and an optionally substituted heterocyclic group (having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring).

Specific examples of the substituent of the substituted aromatic hydrocarbon group having 6 to 14 carbon atoms of R³ include the same as those exemplified in the substituent of the substituted aliphatic hydrocarbon group having 1 to 10 carbon atoms of G².

As the substituent of the substituted aromatic hydrocarbon group having 6 to 14 carbon atoms of R³, a C₁-C₇ alkoxy group, a C₂-C₇ acyl group, a C₂-C₇ alkylcarbamoyl group, a C₁-C₆ alkylamino group, a C₂-C₇ acylamino group, an alicyclic hydrocarbon group having 3 to 6 carbon atoms, an aliphatic hydrocarbon group having 1 to 6 carbon atoms, an aromatic hydrocarbon group having 6 to 14 carbon atoms and a heterocyclic group (having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring), may further be substituted with (one or more substituents selected from the group consisting of: a fluorine atom; a chlorine atom; a bromine atom; an iodine atom; a hydroxy group; a C₁-C₆ alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy or cyclopropyloxy; a methoxymethyloxy group; a 2-methoxyethoxy group; a formyl group; a trifluoroacetyl group; a C₂-C₇ acyl group such as acetyl, propionyl, butyryl, isobutyryl, valeryl or isovaleryl; an oxo group; a carboxyl group; a C₂-C₇ alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl or t-butoxycarbonyl; a carbamoyl group; a C₂-C₇ alkylcarbamoyl group such as N-methylcarbamoyl, N,N-dimethylcarbamoyl, N-ethylcarbamoyl, N-ethyl-N-methylcarbamoyl, N,N-diethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, N-cyclopropyl-carbamoyl or N-cyclopropylmethylcarbamoyl; an amino group; a C₁-C₆ alkylamino group such as methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, N-ethylmethyl-amino, diethylamino, N-methylpropylamino, N-methylisopropyl-amino, cyclopropylamino or cyclopropylmethylamino; a C₄-C₆ cyclic amino group having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, such as 1-pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, piperidino or morpholino; a trifluoroacetylamino group; a C₁-C₇ acylamino group such as formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino or valerylamino; a C₁-C₆ alkylsulfonylamino group such as methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino or butylsulfonylamino; a nitro group; a cyano group; a C₁-C₆ alkyl group including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, and t-butyl; a trifluoromethyl group; and a trifluoromethoxy group).

In the formula (I), when R³ represents a heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on its substituted or unsubstituted ring, examples of such heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on the ring of R³ include the same as those exemplified in the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on the ring of G².

The heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on the ring of R³ links to A⁶ on a carbon atom or a nitrogen atom.

Preferred examples of the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on the ring of R³ and linking to A⁶ on a carbon atom, include a monocyclic or bicyclic C₃-C₉ aromatic heterocyclic group having 1 to 3 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, including furyl, thienyl, pyrrolyl, pyrazolyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyridyl, N-oxopyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzofuranyl, indolyl, benzothienyl, quinolyl, isoquinolyl, quinazolyl, benzoimidazolyl and benzooxazolyl, preferably 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 2-oxazolyl, 2-thiazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-N-oxopyridyl, 3-N-oxopyridyl, 4-N-oxopyridyl, 3-pyrazolyl, 4-pyrazolyl, 4-imidazolyl, 2-pyrimidinyl, or 5-pyrimidinyl.

Meanwhile, preferred examples of the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on the ring of R³ and linking to A⁶ on a nitrogen atom, include 1-imidazolyl, 1-pyrazolyl, 1-pyrrolyl, 1-pyrrolidinyl, piperidino, morpholino, 1-homopiperidinyl and 1-piperazinyl, preferably 1-imidazolyl.

When the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on the ring of R³ links to A⁶ on a nitrogen atom, A⁶ is a single bond, or a group that links a carbon atom of a pyrrole ring in which R³ and A⁶ are linked to each other in the form of R³—C(═O)-pyrrole ring.

Exemplary substituents of the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on the ring of R³ include at least one substituent selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a hydroxy group, an optionally substituted C₁-C₇ alkoxy group, a C₆-C₁₀ aryloxy group, a C₇-C₉ aralkoxy group, a C₂-C₇ acyloxy group, an oxo group, a C₁-C₆ alkylsulfonyloxy group, an optionally substituted C₂-C₇ acyl group, a carboxyl group, a C₂-C₇ alkoxycarbonyl group, a carbamoyl group, an optionally substituted C₂-C₇ alkylcarbamoyl group, an amino group, an optionally substituted C₁-C₆ alkylamino group, an optionally substituted C₂-C₇ acylamino group, a C₂-C₈ alkoxycarbonylamino group, a C₁-C₆ alkylsulfonylamino group, a cyano group, a nitro group, a C₁-C₆ alkylthio group, a C₁-C₆ alkylsulfynyl group, a C₁-C₆ alkylsulfonyl group, a sulfamoyl group, a C₁-C₆ alkylaminosulfonyl group, a sulfo group, an optionally substituted alicyclic hydrocarbon group having 3 to 6 carbon atoms, an optionally substituted aliphatic hydrocarbon group having 1 to 6 carbon atoms, an optionally substituted aromatic hydrocarbon group having 6 to 14 carbon atoms and an optionally substituted heterocyclic group (having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring).

Specific examples of the substituent of the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on its substituted ring of R³ include the same as those exemplified in the substituted aliphatic hydrocarbon group having 1 to 10 carbon atoms of G².

As the substituent of the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on its substituted ring of R³, a C₁-C₇ alkoxy group, a C₂-C₇ acyl group, a C₂-C₇ alkylcarbamoyl group, a C₁-C₆ alkylamino group, a C₂-C₇ acylamino group, an alicyclic hydrocarbon group having 3 to 6 carbon atoms and an aliphatic hydrocarbon group having 1 to 6 carbon atoms, an aromatic hydrocarbon group having 6 to 14 carbon atoms, and a heterocyclic group (having 1 to 4 atoms selected from the group consisting of oxygen atom, a nitrogen atom and a sulfur atom in the ring) may further be substituted with (one or more substituents selected from the group consisting of: a fluorine atom; a chlorine atom; a bromine atom; an iodine atom; a hydroxy group; a C₁-C₆ alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy or cyclopropyloxy; a methoxymethyloxy group; a 2-methoxyethoxy group; a formyl group; a trifluoroacetyl group; a C₂-C₇ acyl group such as acetyl, propionyl, butyryl, isobutyryl, valeryl or isovaleryl; an oxo group; a carboxyl group; a C₂-C₇ alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl or t-butoxycarbonyl; a carbamoyl group; a C₂-C₇ alkylcarbamoyl group such as N-methylcarbamoyl, N,N-dimethylcarbamoyl, N-ethylcarbamoyl, N-ethyl-N-methylcarbamoyl, N,N-diethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, N-cyclopropyl-carbamoyl or N-cyclopropylmethylcarbamoyl; an amino group; a C₁-C₆ alkylamino group such as methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, N-ethylmethylamino, diethylamino, N-methylpropylamino, N-methylisopropylamino, cyclopropylamino or cyclopropylmethylamino; a C₄-C₆ cyclic amino group having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, such as 1-pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, piperidino or morpholino; a trifluoroacetylamino group; a C₁-C₇ acylamino group such as formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino or valerylamino; a C₁-C₆-alkylsulfonylamino group such as methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino or butylsulfonylamino; a nitro group; a cyano group; a C₁-C₆ alkyl group including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, and t-butyl; a trifluoromethyl group; and a trifluoromethoxy group).

Among those exemplified as substituents of the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on the ring of R³, preferred examples thereof include: a fluorine atom; a chlorine atom; a bromine atom; an iodine atom; a hydroxy group; a cyano group; a nitro group; an amino group; a C₁-C₆ mono or dialkylamino group consisting of a straight or branched alkyl group and an amino group, including a substituted or unsubstituted methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, s-butylamino, t-butylamino, pentylamino, hexylamino, dimethylamino, N-ethylmethylamino, diethylamino, N-methylpropylamino, N-methylisopropylamino, N-methylbutylamino, N-methyl-t-butylamino, N-ethylisopropylamino, dipropylamino, diisopropylamino and ethylbutylamino; a carboxyl group; a saturated a C₁-C₆ alkyl group including a substituted or unsubstituted methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, neopentyl, t-pentyl, hexyl, isohexyl, 2-methylpentyl and 1-ethylbutyl; an alicyclic hydrocarbon group having 3 to 6 carbon atoms including cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; a C₁-C₆ alkoxy group consisting of a straight or branched alkyl group and an oxy group, including a substituted or unsubstituted methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy, t-pentyloxy and hexyloxy; a C₂-C₇ acyl group including a substituted or unsubstituted acetyl, propionyl, butyryl, isobutyryl, pivaroyl and hexanoyl; a C₁-C₆ alkylthio group, including methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, s-butylthio, t-butylthio, pentylthio and hexylthio; a trifluoromethyl group; a trifluoromethoxy group; a C₂-C₇ acylamino group including a substituted or unsubstituted acetylamino, propionylamino, butyrylamino, isobutyrylamino, valerylamino and hexanoylamino; and a C₂-C₇ alkylcarbamoyl group consisting of a straight or branched alkyl group and a carbamoyl group including a substituted or unsubstituted N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, N-isobutylcarbamoyl, N-s-butylcarbamoyl, N-t-butylcarbamoyl, N-pentylcarbamoyl, N,N-dimethylcarbamoyl, N-ethyl-N-methylcarbamoyl and N,N-diethylcarbamoyl.

More preferred substituents of the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on the ring of R³, include a fluorine atom, a chlorine atom, a bromine atom, a substituted or unsubstituted C₁-C₆ alkyl group, a hydroxy group, and a substituted or unsubstituted C₁-C₆ alkoxy group. Specifically, a methyl group and an ethyl group are preferred.

In the formula (I), A⁶ is a group that links R³ and a carbon atom of a pyrrole ring in the form of R³—CR³⁰⁸═CR³⁰⁹-pyrrole ring or R³—C≡C-pyrrole ring. R³ represents a trimethylsilyl group, a formyl group, an optionally substituted C₂-C₇ acyl group, a carboxyl group, a C₂-C₇ alkoxycarbonyl group, a carbamoyl group, an optionally substituted C₂-C₇ alkylcarbamoyl group or a cyano group, preferred examples thereof include a formyl group, an acetyl group, a carboxyl group, a methoxycarbonyl group, an ethoxycarbonyl group and a cyano group.

Here, an explanation will be given of preferred combinations of R³ and A⁶ in the formula (I).

As combinations of R³ and A⁶ of the formula (I) in the present invention, when R³ represents a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, A³ represents a single bond.

Also, when R³ represents a trimethylsilyl group, a formyl group, an optionally substituted a C₂-C₇ acyl group, a carboxyl group, a C₂-C₇ alkoxycarbonyl group, a carbamoyl group, an optionally substituted C₂-C₇ alkylcarbamoyl group, or a cyano group, A is a group that links a carbon atom of a pyrrole ring in which R³ and A⁶ are linked to each other in the form of a carbon atom of R³—CR³⁰⁸═CR³⁰⁹-pyrrole ring or R³—C≡C-pyrrole carbon atom.

Preferred combinations of R³ and A⁶ of the formula (I) in the present invention include cases where A⁶ represents a single bond and R³ represents an optionally substituted aromatic hydrocarbon group having 6 to 14 carbon atoms or an optionally substituted heterocyclic group. Among them, a case where R³ represents a thienyl group, a furyl group, a pyrrolyl group, a pyrazolyl group or a phenyl group optionally substituted with one or more alkyl group having 1 to 4 carbon atoms is preferred.

Also a case where A⁶ represents a single bond, and R³ represents a pyridyl group or 1-oxypyridyl group or pyrazolyl group or N-methylpyrazolyl group optionally substituted by an alkyl group having 1 to 4 carbon atoms or one halogen atom.

In addition, the following combinations can be mentioned: a combination in which A⁶ represents a single bond, and R³ is a fluorine atom, chlorine atom, bromine atom, or iodine atom, a combination in which A⁶ represents a single bond, and R³ is a substituted or unsubstituted saturated acyclic saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms; a combination in which A⁶ represents a single bond, and R³ is a substituted or unsubstituted alicyclic hydrocarbon group having 3 to 8 carbon atoms; a combination in which A⁶ represents a single bond, and R³ is a substituted or unsubstituted aromatic hydrocarbon group having 6 to 14 carbon atoms; a combination in which A⁶ represents a single bond, and R³ is a substituted or unsubstituted monocyclic C₃-C₅ aromatic heterocyclic group having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring; a combination in which A⁶ is a group that links R³ and a carbon atom of a pyrrole ring in which A⁶ is linked in the form of the carbon atom of a R³—NH—C(═O)-pyrrole ring, and R³ is a hydrogen atom; a combination in which A⁶ is a group that links R³ and a carbon atom of a pyrrole ring in which A⁶ is linked in the form of the carbon atom of a R³—C(═O)—NH-pyrrole ring, and R³ is a substituted or unsubstituted acyclic acyclic saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms; a combination in which A⁶ is a group that links R³ and a carbon atom of a pyrrole ring in which A⁶ is linked in the form of the carbon atom of the carbon atom of a R³—C(═O)—NH-pyrrole ring, and R³ is a substituted or unsubstituted alicyclic hydrocarbon group having 3 to 8 carbon atoms; a combination in which A⁶ is a group that links R³ and a carbon atom of a pyrrole ring in which A⁶ is linked in the form of the carbon atom of a R³—C(═O)—NH-pyrrole ring, and R³ is a substituted or unsubstituted aromatic hydrocarbon group having 6 to 14 carbon atoms; a combination in which A⁶ is a group that links R³ and a carbon atom of a pyrrole ring in which A⁶ is linked in the form of the carbon atom of the R³—C(═O)—NH-pyrrole ring, and R³ is a monocyclic C₃-C₅ aromatic heterocyclic group having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on the substituted or unsubstituted ring; a combination in which A⁶ is a group that links R³ and a carbon atom of a pyrrole ring in which A⁶ is linked in the form of the carbon atom of a R³—NH-pyrrole ring, and R³ is a hydrogen atom; a combination in which A⁶ is a group that links R³ and a carbon atom of a pyrrole ring in which A⁶ is linked in the form of the carbon atom of a R³—NH-pyrrole ring, and R³ is a substituted or unsubstituted acyclic saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms; a combination in which A⁶ is a group that links R³ and a carbon atom of a pyrrole ring in which A⁶ is linked in the form of the carbon atom of a R³—NH-pyrrole ring, and R³ is a substituted or unsubstituted alicyclic hydrocarbon group having 3 to 8 carbon atoms; a combination in which A⁶ is a group that links R³ and a carbon atom of a pyrrole ring in which A⁶ is linked in the form of the carbon atom of a R³—NH-pyrrole ring, and R³ is a substituted or unsubstituted aromatic hydrocarbon group having 6 to 14 carbon atoms; a combination in which A⁶ is a group that links R³ and a carbon atom of a pyrrole ring in which A⁶ is linked in the form of the carbon atom of R³—NH-pyrrole ring, and R³ is a monocyclic C₃-C₅ aromatic heterocyclic group having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on the substituted or unsubstituted ring; a combination in which A⁶ is a group that links R³ and a carbon atom of a pyrrole ring in which A⁶ is linked in the form of the carbon atom of a R³—HC═CH-pyrrole ring, and R³ is a hydrogen atom; a combination in which A⁶ is a group that links R³ and a carbon atom of a pyrrole ring in which A⁶ is linked to each other in the form of the carbon atom of a R³—HC═CH-pyrrole ring, and R³ is a substituted or unsubstituted acyclic saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms; a combination in which A⁶ is a group that links a carbon atom of a pyrrole ring in which R³ and A⁶ are linked to each other in the form of the carbon atom of a R³—HC═CH-pyrrole ring, and R³ is a substituted or unsubstituted alicyclic hydrocarbon group having 3 to 8 carbon atoms; a combination in which A⁶ is a group that links R³ and a carbon atom of a pyrrole ring in which A⁶ is linked in the form of the carbon atom of a R³—HC═CH-pyrrole ring, and R³ is a substituted or unsubstituted aromatic hydrocarbon group having 6 to 14 carbon atoms; a combination in which A⁶ is a group that links R³ and a carbon atom of a pyrrole ring in which A⁶ is linked in the form of the carbon atom of a R³—HC═CH-pyrrole ring, and R³ is a monocyclic C₃-C₅-aromatic heterocyclic group having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on the substituted or unsubstituted ring; a combination in which A⁶ is a group that links R³ and a carbon atom of a pyrrole ring in which A⁶ is linked in the form of the carbon atom of a R³—C≡C-pyrrole ring, and R³ is a hydrogen atom; a combination in which A⁶ is a group that links R³ and a carbon atom of a pyrrole ring in which A⁶ is linked in the form of the carbon atom of a R³—C≡C-pyrrole ring, and R³ is a substituted or unsubstituted acyclic saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms; a combination in which A⁶ is a group that links R³ and a carbon atom of a pyrrole ring in which A⁶ is linked in the form of the carbon atom of a R³—C≡C-pyrrole ring, and R³ is a substituted or unsubstituted alicyclic hydrocarbon group having 3 to 8 carbon atoms; a combination in which A⁶ is a group that links R³ and a carbon atom of a pyrrole ring in which A⁶ is linked in the form of the carbon atom of a R³—C≡C-pyrrole ring, and R³ is a substituted or unsubstituted aromatic hydrocarbon group having 6 to 14 carbon atoms; a combination in which A⁶ is a group that links R³ and a carbon atom of a pyrrole ring in which A⁶ is linked in the form of the carbon atom of a R³—C≡C-pyrrole ring, and R³ is a monocyclic C₃-C₅ aromatic heterocyclic group having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on the substituted or unsubstituted ring; and a combination in which A⁶ is a group that links R³ and a carbon atom of a pyrrole ring in which A⁶ is linked in the form of the carbon atom of a R³—C≡C-pyrrole ring, and R³ is a trimethylsilyl group or cyano group.

Here, an explanation will be given of preferred combinations of R²-A⁵ portion and R³-A⁶ portion in the formula (I).

Preferred combinations of R²-A⁵ portion and R³-A⁶ portion include cases where both of A⁵ and A⁶ represent a single bond. In this case, more preferred combinations include cases where R² represents a cyclopropyl group, a cyclobutyl group, a cyclopropylmethyl group, a methyl group, an ethyl group, a vinyl group, an isopropyl group, an isobutyl group or 2-methyl-1-propenyl group, and R³ represents a pyridyl group or 1-oxypyridyl group or pyrazolyl group or N-methylpyrazolyl group optionally substituted with one alkyl group having 1 to 4 carbon atoms or one halogen atom.

Also combinations wherein both of A⁵ and A⁶ represent a single bond, and R² represents a C₁-C₄ alkyl group, a C₁-C₄ alkoxy group, a C₂-C₄ acyl group, a hydroxy group, a carboxyl group, an alkoxycarbonyl group, a thienyl group, a pyridyl group, a furyl group, a pyrrolyl group, a pyrazolyl group or phenyl group which may be substituted by one or more of a fluorine atom or a chlorine atom, and R³ represents a pyridyl group or 1-oxypyridyl group or pyrazolyl group or N-methylpyrazolyl group which may be substituted by one alkyl group having 1 to 4 carbon atoms or one halogen atom can be mentioned as preferred examples.

Further, an explanation will be given of preferred combinations of A¹-G² portion, R²-A⁵ portion and R³-A⁶ portion in the formula (I). Basically, preferably those mentioned as preferred examples for A¹-G² portion, R²-A⁵ portion and R³-A⁶ portion are combined, and more preferably more preferred examples are combined.

More specifically, in the combinations of the following a) to f) mentioned as preferred combinations of the A¹-G² portion, further a case where both of A⁵ and A⁶ represent a single bond is preferred.

a) A¹ represents —(CH₂)₂— or —(CH₂)₃—, A² represents —NH—(C═O)— or —NH—(C═O)—NH—, G¹ represents a single bond, and A³ represents a divalent acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms.

b) A¹ represents —(CH₂)₂— or —(CH₂)₃—, A² represents —NH—(C═O)—, —NH—(C═O)—NH—, —NH—, or —C—(═O)—NH—, and G¹ represents a group other than the single bond.

c) A¹ represents a divalent acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms, specifically —(CH₂)₂— or —(CH₂)₃—, A² represents a single bond, and G¹ represents an optionally substituted heterocyclic group (note, where a heterocyclic group of G¹ is 5 or 6 membered monocyclic ring, 5 or 6 membered monocyclic heterocyclic group of G¹ is substituted, or A³-G² portion represents those other than a hydrogen atom).

d) A¹ represents a divalent acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms, specifically —(CH₂)₂— or —(CH₂)₃—, A² represents those other than a single bond, and G¹ represents an optionally substituted aromatic hydrocarbon group, an optionally substituted alicyclic hydrocarbon group having 7 to 10 carbon atoms, or an optionally substituted heterocyclic group (note, where the aromatic hydrocarbon group of G¹ is a phenyl group, or where the heterocyclic group of G¹ is 5 or 6 membered monocyclic ring, the phenyl group of G¹ or 5 or 6 membered monocyclic heterocyclic group is substituted, or A³-G² portion represents those other than a hydrogen atom).

e) A¹ represents a divalent acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms, specifically —(CH₂)₂— or —(CH₂)₃—, A² represents those other than a single bond, G¹ and A⁴ represent the single bond, A³ represents an optionally substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms, G² represents an optionally substituted alicyclic hydrocarbon group having 5 to 10 carbon atoms, an optionally substituted aromatic hydrocarbon group, or optionally substituted heterocyclic group.

f) A¹ represents a divalent acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms, —specifically —(CH₂)₂— or —(CH₂)₃—, A² represents those other than a single bond, G¹ represents the single bond, A³ represents an optionally substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms, and A⁴ represents —C(═O)—, —C(═O)—NR¹²¹—, —C(═S)—NR¹²²—, —C(═NR¹²³)—, —O—C(═O)—, —NR¹²⁵—C(═O)—, —NR¹²⁶ —S(═O)₂—, —NR¹²⁷—C(═O)—O—, —NR¹²⁸—C(═O)—NR¹²⁹—, —NR¹³⁰—C(═S)—, —NR¹³¹—C(═S)—NR¹³²—, —S—, —S(═O)—, —S(═O)₂—, —S(═O)₂—NR¹³³— or —S(═O)₂—O—.

In the cases of d) to f), A² preferably represents —C(═O)—, —C(═O)—O—, —C(═O)—NH—, —C(═O)—NMe-, —NH—, —NH—C(═O)—, —NH—C(═O)—O—, —NH—C(═O)—NH—, —NH—C(═O)—NMe-, or —NH—C(═S)—, especially preferably represents —C(═O)—NH—, —NH—, —NH—C(═O)—, —NH—C(═O)—O—, or —NH—C(═O)—NH—.

In these cases of combinations, further preferably R² represents an optionally substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms, an optionally substituted alicyclic hydrocarbon group having 3 to 8 carbon atoms, an optionally substituted aromatic hydrocarbon group having 6 to 14 carbon atoms or an optionally substituted heterocyclic group, and R³ represents an optionally substituted aromatic hydrocarbon group having 6 to 14 carbon atoms or an optionally substituted heterocyclic group.

In further detail, in these cases, combinations wherein R² represents an aliphatic hydrocarbon group having 1 to 10 carbon atoms, an alicyclic hydrocarbon group having 3 to 8 carbon atoms, an optionally substituted phenyl group, or an optionally substituted heterocyclic group having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, and R³ represents a thienyl group, a pyridyl group, a furyl group, a pyrrolyl group, a pyrazolyl group or a phenyl group optionally substituted with one or more alkyl group having 1 to 4 carbon atoms are specifically preferred. Especially, preferred combinations can include cases where R² represents a cyclopropyl group, a methyl group, an ethyl group, a vinyl group, an isopropyl group, an isobutyl group or 2-methyl-1-propenyl group, and R³ represents a pyridyl group or 1-oxypyridyl group or pyrazolyl group or N-methylpyrazolyl group which may be substituted by an alkyl group having 1 to 4 carbon atoms or one halogen atom, and cases where R² represents a thienyl group, a pyridyl group, a furyl group, a pyrrolyl group, a pyrazolyl group or phenyl group which may be substituted by one or more of a C₁-C₄ alkyl group, a C₁-C₄ alkoxy group, and a chlorine group, and R³ represents a pyridyl group or 1-oxypyridyl group or pyrazolyl group or N-methylpyrazolyl group which may be substituted by an alkyl group having 1 to 4 carbon atoms or one halogen atom.

In the pyrrolo-pyrimidinone derivatives of the formula (I), specific preferred combinations of -G¹-A³-A⁴-G² portion include groups represented by the following formulae, K001-K431. In the respective chemical formula, symbol “ - - -” is used to denote a binding site between A² and the group -G¹-A³-A⁴-G².

In the pyrrolo-pyrimidinone derivatives of the formula (I), as specific examples of preferred combinations of the -A⁵-R² portion, groups represented by the following formulae, J001-J166 may be mentioned. In the respective chemical formulae, symbol “ - - -” indicates a binding site between a carbon atom of a pyrrole ring and -A⁵-R².

In the pyrrolo-pyrimidinone derivatives of the formula (I), as specific examples of preferred combinations of the -A⁶-R³ portion, groups represented by the following formulae, T001-T181 may be mentioned. In the respective chemical formulae, symbol “ - - -” indicates a binding site between a carbon atom of a pyrrole ring and -A⁶-R³.

Specific examples of the pyrrolo-pyrimidinone derivatives of formula (I) include the compounds having groups described in the following Table 1 as A¹, the compounds having groups described in the following Table 1 as A², the compounds having groups represented by K001-K431 indicated in the formula as -G¹-A³-A⁴-G², the compounds having groups represented by J01-J166 indicated in the formula as -A⁵-R², the compounds having groups represented by T001-T181 indicated in the formula as -A⁶-R³, and the compounds consisting of any combination of groups mentioned above with regard to each moiety. Preferable examples among such compounds are listed in Tables below.

TABLE 1
Compound
no.	-A1-	-A2-	-G1-A3-A4-G2	-A5-R2	-A6-R3
1	—(CH2)2—	—C(═O)—	K002	J001	T148
2	—(CH2)2—	—C(═O)—	K002	J001	T151
3	—(CH2)2—	—C(═O)—	K003	J001	T148
4	—(CH2)2—	—C(═O)—	K003	J001	T151
5	—(CH2)2—	—C(═O)—	K004	J001	T148
6	—(CH2)2—	—C(═O)—	K004	J001	T151
7	—(CH2)2—	—C(═O)—	K005	J001	T148
8	—(CH2)2—	—C(═O)—	K005	J001	T151
9	—(CH2)2—	—C(═O)—	K007	J001	T148
10	—(CH2)2—	—C(═O)—	K007	J001	T152
11	—(CH2)2—	—C(═O)—	K008	J001	T148
12	—(CH2)2—	—C(═O)—	K008	J001	T152
13	—(CH2)2—	—C(═O)—	K009	J001	T148
14	—(CH2)2—	—C(═O)—	K009	J001	T152
15	—(CH2)2—	—C(═O)—	K012	J001	T148
16	—(CH2)2—	—C(═O)—	K012	J001	T152
17	—(CH2)2—	—C(═O)—	K107	J001	T148
18	—(CH2)2—	—C(═O)—	K107	J001	T168
19	—(CH2)2—	—C(═O)—	K108	J001	T148
20	—(CH2)2—	—C(═O)—	K108	J001	T169
21	—(CH2)2—	—C(═O)—	K112	J001	T148
22	—(CH2)2—	—C(═O)—	K112	J001	T170
23	—(CH2)2—	—C(═O)—	K129	J001	T148
24	—(CH2)2—	—C(═O)—	K129	J001	T171
25	—(CH2)2—	—C(═O)—	K133	J001	T148
26	—(CH2)2—	—C(═O)—	K133	J001	T172
27	—(CH2)2—	—C(═O)—	K137	J001	T148
28	—(CH2)2—	—C(═O)—	K137	J001	T173
29	—(CH2)2—	—C(═O)—NH—	K007	J001	T148
30	—(CH2)2—	—C(═O)—NH—	K012	J001	T148
31	—(CH2)2—	—C(═O)—O—	K001	J001	T148
32	—(CH2)2—	—C(═O)—O—	K002	J001	T151
33	—(CH2)2—	—C(═O)—O—	K193	J001	T152
34	—(CH2)2—	—C(═O)—O—	K227	J001	T169
35	—(CH2)2—	—C(═O)—O—	K002	J001	T148
36	—(CH2)2—	—NH—	K181	J012	T148
37	—(CH2)2—	—NH—	K181	J012	T151
38	—(CH2)2—	—NH—	K181	J012	T152
39	—(CH2)2—	—NH—	K181	J012	T169
40	—(CH2)2—	—NH—	K181	J045	T148
41	—(CH2)2—	—NH—	K181	J045	T151
42	—(CH2)2—	—NH—	K181	J045	T152
43	—(CH2)2—	—NH—	K181	J045	T169
44	—(CH2)2—	—NH—	K181	J045	T170
45	—(CH2)2—	—NH—	K181	J045	T172
46	—(CH2)2—	—NH—	K182	J012	T148
47	—(CH2)2—	—NH—	K182	J012	T151
48	—(CH2)2—	—NH—	K182	J012	T152
49	—(CH2)2—	—NH—	K182	J012	T169
50	—(CH2)2—	—NH—	K182	J045	T148
51	—(CH2)2—	—NH—	K182	J045	T151
52	—(CH2)2—	—NH—	K182	J045	T152
53	—(CH2)2—	—NH—	K182	J045	T169
54	—(CH2)2—	—NH—	K182	J045	T170
55	—(CH2)2—	—NH—	K182	J045	T172
56	—(CH2)2—	—NH—	K183	J012	T148
57	—(CH2)2—	—NH—	K183	J012	T151
58	—(CH2)2—	—NH—	K183	J012	T152
59	—(CH2)2—	—NH—	K183	J012	T169
60	—(CH2)2—	—NH—	K183	J045	T148
61	—(CH2)2—	—NH—	K183	J045	T151
62	—(CH2)2—	—NH—	K183	J045	T152
63	—(CH2)2—	—NH—	K183	J045	T169
64	—(CH2)2—	—NH—	K183	J045	T170
65	—(CH2)2—	—NH—	K183	J045	T172
66	—(CH2)2—	—NH—	K184	J012	T148
67	—(CH2)2—	—NH—	K184	J012	T151
68	—(CH2)2—	—NH—	K184	J012	T152
69	—(CH2)2—	—NH—	K184	J012	T169
70	—(CH2)2—	—NH—	K184	J045	T148
71	—(CH2)2—	—NH—	K184	J045	T151
72	—(CH2)2—	—NH—	K184	J045	T152
73	—(CH2)2—	—NH—	K184	J045	T169
74	—(CH2)2—	—NH—	K184	J045	T170
75	—(CH2)2—	—NH—	K184	J045	T172
76	—(CH2)2—	—NH—	K185	J012	T148
77	—(CH2)2—	—NH—	K185	J012	T151
78	—(CH2)2—	—NH—	K185	J012	T152
79	—(CH2)2—	—NH—	K185	J012	T169
80	—(CH2)2—	—NH—	K185	J045	T004
81	—(CH2)2—	—NH—	K185	J045	T005
82	—(CH2)2—	—NH—	K185	J045	T090
83	—(CH2)2—	—NH—	K185	J045	T129
84	—(CH2)2—	—NH—	K185	J045	T148
85	—(CH2)2—	—NH—	K185	J045	T151
86	—(CH2)2—	—NH—	K185	J045	T152
87	—(CH2)2—	—NH—	K185	J045	T169
88	—(CH2)2—	—NH—	K185	J045	T170
89	—(CH2)2—	—NH—	K185	J045	T172
90	—(CH2)2—	—NH—	K186	J012	T148
91	—(CH2)2—	—NH—	K186	J012	T151
92	—(CH2)2—	—NH—	K186	J012	T152
93	—(CH2)2—	—NH—	K186	J012	T169
94	—(CH2)2—	—NH—	K186	J045	T148
95	—(CH2)2—	—NH—	K186	J045	T151
96	—(CH2)2—	—NH—	K186	J045	T152
97	—(CH2)2—	—NH—	K186	J045	T169
98	—(CH2)2—	—NH—	K186	J045	T170
99	—(CH2)2—	—NH—	K186	J045	T172
100	—(CH2)2—	—NH—	K187	J012	T148
101	—(CH2)2—	—NH—	K187	J012	T151
102	—(CH2)2—	—NH—	K187	J012	T152
103	—(CH2)2—	—NH—	K187	J012	T169
104	—(CH2)2—	—NH—	K187	J045	T148
105	—(CH2)2—	—NH—	K187	J045	T151
106	—(CH2)2—	—NH—	K187	J045	T152
107	—(CH2)2—	—NH—	K187	J045	T169
108	—(CH2)2—	—NH—	K187	J045	T170
109	—(CH2)2—	—NH—	K187	J045	T172
110	—(CH2)2—	—NH—	K188	J012	T148
111	—(CH2)2—	—NH—	K188	J012	T151
112	—(CH2)2—	—NH—	K188	J012	T152
113	—(CH2)2—	—NH—	K188	J012	T169
114	—(CH2)2—	—NH—	K188	J045	T148
115	—(CH2)2—	—NH—	K188	J045	T151
116	—(CH2)2—	—NH—	K188	J045	T152
117	—(CH2)2—	—NH—	K188	J045	T169
118	—(CH2)2—	—NH—	K188	J045	T170
119	—(CH2)2—	—NH—	K188	J045	T172
120	—(CH2)2—	—NH—	K189	J012	T148
121	—(CH2)2—	—NH—	K189	J012	T151
122	—(CH2)2—	—NH—	K189	J012	T152
123	—(CH2)2—	—NH—	K189	J012	T169
124	—(CH2)2—	—NH—	K189	J045	T148
125	—(CH2)2—	—NH—	K189	J045	T151
126	—(CH2)2—	—NH—	K189	J045	T152
127	—(CH2)2—	—NH—	K189	J045	T169
128	—(CH2)2—	—NH—	K189	J045	T170
129	—(CH2)2—	—NH—	K189	J045	T172
130	—(CH2)2—	—NH—	K190	J012	T148
131	—(CH2)2—	—NH—	K190	J012	T151
132	—(CH2)2—	—NH—	K190	J012	T152
133	—(CH2)2—	—NH—	K190	J012	T169
134	—(CH2)2—	—NH—	K190	J045	T148
135	—(CH2)2—	—NH—	K190	J045	T151
136	—(CH2)2—	—NH—	K190	J045	T152
137	—(CH2)2—	—NH—	K190	J045	T169
138	—(CH2)2—	—NH—	K190	J045	T170
139	—(CH2)2—	—NH—	K190	J045	T172
140	—(CH2)2—	—NH—	K191	J012	T148
141	—(CH2)2—	—NH—	K191	J012	T151
142	—(CH2)2—	—NH—	K191	J012	T152
143	—(CH2)2—	—NH—	K191	J012	T169
144	—(CH2)2—	—NH—	K191	J045	T148
145	—(CH2)2—	—NH—	K191	J045	T151
146	—(CH2)2—	—NH—	K191	J045	T152
147	—(CH2)2—	—NH—	K191	J045	T169
148	—(CH2)2—	—NH—	K191	J045	T170
149	—(CH2)2—	—NH—	K191	J045	T172
150	—(CH2)2—	—NH—	K192	J012	T148
151	—(CH2)2—	—NH—	K192	J012	T151
152	—(CH2)2—	—NH—	K192	J012	T152
153	—(CH2)2—	—NH—	K192	J012	T169
154	—(CH2)2—	—NH—	K192	J045	T148
155	—(CH2)2—	—NH—	K192	J045	T151
156	—(CH2)2—	—NH—	K192	J045	T152
157	—(CH2)2—	—NH—	K192	J045	T169
158	—(CH2)2—	—NH—	K192	J045	T170
159	—(CH2)2—	—NH—	K192	J045	T172
160	—(CH2)2—	—NH—	K193	J012	T148
161	—(CH2)2—	—NH—	K193	J012	T151
162	—(CH2)2—	—NH—	K193	J012	T152
163	—(CH2)2—	—NH—	K193	J012	T169
164	—(CH2)2—	—NH—	K193	J045	T148
165	—(CH2)2—	—NH—	K193	J045	T151
166	—(CH2)2—	—NH—	K193	J045	T152
167	—(CH2)2—	—NH—	K193	J045	T169
168	—(CH2)2—	—NH—	K193	J045	T170
169	—(CH2)2—	—NH—	K193	J045	T172
170	—(CH2)2—	—NH—	K194	J012	T148
171	—(CH2)2—	—NH—	K194	J012	T151
172	—(CH2)2—	—NH—	K194	J012	T152
173	—(CH2)2—	—NH—	K194	J012	T169
174	—(CH2)2—	—NH—	K194	J045	T148
175	—(CH2)2—	—NH—	K194	J045	T151
176	—(CH2)2—	—NH—	K194	J045	T152
177	—(CH2)2—	—NH—	K194	J045	T169
178	—(CH2)2—	—NH—	K194	J045	T170
179	—(CH2)2—	—NH—	K194	J045	T172
180	—(CH2)2—	—NH—	K195	J012	T148
181	—(CH2)2—	—NH—	K195	J012	T151
182	—(CH2)2—	—NH—	K195	J012	T152
183	—(CH2)2—	—NH—	K195	J012	T169
184	—(CH2)2—	—NH—	K195	J045	T148
185	—(CH2)2—	—NH—	K195	J045	T151
186	—(CH2)2—	—NH—	K195	J045	T152
187	—(CH2)2—	—NH—	K195	J045	T169
188	—(CH2)2—	—NH—	K195	J045	T170
189	—(CH2)2—	—NH—	K195	J045	T172
190	—(CH2)2—	—NH—	K196	J012	T148
191	—(CH2)2—	—NH—	K196	J012	T151
192	—(CH2)2—	—NH—	K196	J012	T152
193	—(CH2)2—	—NH—	K196	J012	T169
194	—(CH2)2—	—NH—	K196	J045	T148
195	—(CH2)2—	—NH—	K196	J045	T151
196	—(CH2)2—	—NH—	K196	J045	T152
197	—(CH2)2—	—NH—	K196	J045	T169
198	—(CH2)2—	—NH—	K196	J045	T170
199	—(CH2)2—	—NH—	K196	J045	T172
200	—(CH2)2—	—NH—	K197	J012	T148
201	—(CH2)2—	—NH—	K197	J012	T151
202	—(CH2)2—	—NH—	K197	J012	T152
203	—(CH2)2—	—NH—	K197	J012	T169
204	—(CH2)2—	—NH—	K197	J045	T003
205	—(CH2)2—	—NH—	K197	J045	T004
206	—(CH2)2—	—NH—	K197	J045	T005
207	—(CH2)2—	—NH—	K197	J045	T077
208	—(CH2)2—	—NH—	K197	J045	T090
209	—(CH2)2—	—NH—	K197	J045	T148
210	—(CH2)2—	—NH—	K197	J045	T151
211	—(CH2)2—	—NH—	K197	J045	T152
212	—(CH2)2—	—NH—	K197	J045	T161
213	—(CH2)2—	—NH—	K197	J045	T169
214	—(CH2)2—	—NH—	K197	J045	T170
215	—(CH2)2—	—NH—	K197	J045	T172
216	—(CH2)2—	—NH—C(═O)—	K001	J001	T129
217	—(CH2)2—	—NH—C(═O)—	K001	J045	T148
218	—(CH2)2—	—NH—C(═O)—	K002	J002	T130
219	—(CH2)2—	—NH—C(═O)—	K002	J045	T148
220	—(CH2)2—	—NH—C(═O)—	K003	J001	T148
221	—(CH2)2—	—NH—C(═O)—	K003	J001	T169
222	—(CH2)2—	—NH—C(═O)—	K003	J008	T134
223	—(CH2)2—	—NH—C(═O)—	K003	J008	T148
224	—(CH2)2—	—NH—C(═O)—	K003	J009	T148
225	—(CH2)2—	—NH—C(═O)—	K003	J012	T148
226	—(CH2)2—	—NH—C(═O)—	K003	J018	T148
227	—(CH2)2—	—NH—C(═O)—	K003	J018	T152
228	—(CH2)2—	—NH—C(═O)—	K003	J035	T148
229	—(CH2)2—	—NH—C(═O)—	K003	J035	T151
230	—(CH2)2—	—NH—C(═O)—	K003	J045	T148
231	—(CH2)2—	—NH—C(═O)—	K003	J052	T148
232	—(CH2)2—	—NH—C(═O)—	K003	J052	T169
233	—(CH2)2—	—NH—C(═O)—	K003	J069	T148
234	—(CH2)2—	—NH—C(═O)—	K003	J069	T152
235	—(CH2)2—	—NH—C(═O)—	K004	J003	T148
236	—(CH2)2—	—NH—C(═O)—	K004	J003	T152
237	—(CH2)2—	—NH—C(═O)—	K004	J008	T148
238	—(CH2)2—	—NH—C(═O)—	K004	J009	T135
239	—(CH2)2—	—NH—C(═O)—	K004	J009	T148
240	—(CH2)2—	—NH—C(═O)—	K004	J012	T148
241	—(CH2)2—	—NH—C(═O)—	K004	J020	T148
242	—(CH2)2—	—NH—C(═O)—	K004	J020	T151
243	—(CH2)2—	—NH—C(═O)—	K004	J037	T148
244	—(CH2)2—	—NH—C(═O)—	K004	J037	T169
245	—(CH2)2—	—NH—C(═O)—	K004	J045	T148
246	—(CH2)2—	—NH—C(═O)—	K004	J054	T148
247	—(CH2)2—	—NH—C(═O)—	K004	J054	T152
248	—(CH2)2—	—NH—C(═O)—	K004	J071	T148
249	—(CH2)2—	—NH—C(═O)—	K004	J071	T151
250	—(CH2)2—	—NH—C(═O)—	K005	J008	T148
251	—(CH2)2—	—NH—C(═O)—	K005	J009	T148
252	—(CH2)2—	—NH—C(═O)—	K005	J012	T145
253	—(CH2)2—	—NH—C(═O)—	K005	J012	T148
254	—(CH2)2—	—NH—C(═O)—	K005	J045	T148
255	—(CH2)2—	—NH—C(═O)—	K006	J008	T148
256	—(CH2)2—	—NH—C(═O)—	K006	J009	T148
257	—(CH2)2—	—NH—C(═O)—	K006	J012	T148
258	—(CH2)2—	—NH—C(═O)—	K006	J014	T148
259	—(CH2)2—	—NH—C(═O)—	K007	J004	T148
260	—(CH2)2—	—NH—C(═O)—	K007	J004	T169
261	—(CH2)2—	—NH—C(═O)—	K007	J008	T148
262	—(CH2)2—	—NH—C(═O)—	K007	J009	T148
263	—(CH2)2—	—NH—C(═O)—	K007	J012	T148
264	—(CH2)2—	—NH—C(═O)—	K007	J015	T149
265	—(CH2)2—	—NH—C(═O)—	K007	J021	T148
266	—(CH2)2—	—NH—C(═O)—	K007	J021	T152
267	—(CH2)2—	—NH—C(═O)—	K007	J038	T148
268	—(CH2)2—	—NH—C(═O)—	K007	J038	T151
269	—(CH2)2—	—NH—C(═O)—	K007	J045	T148
270	—(CH2)2—	—NH—C(═O)—	K007	J055	T148
271	—(CH2)2—	—NH—C(═O)—	K007	J055	T169
272	—(CH2)2—	—NH—C(═O)—	K007	J072	T148
273	—(CH2)2—	—NH—C(═O)—	K007	J072	T152
274	—(CH2)2—	—NH—C(═O)—	K008	J005	T148
275	—(CH2)2—	—NH—C(═O)—	K008	J005	T151
276	—(CH2)2—	—NH—C(═O)—	K008	J008	T148
277	—(CH2)2—	—NH—C(═O)—	K008	J008	T152
278	—(CH2)2—	—NH—C(═O)—	K008	J009	T148
279	—(CH2)2—	—NH—C(═O)—	K008	J009	T152
280	—(CH2)2—	—NH—C(═O)—	K008	J012	T148
281	—(CH2)2—	—NH—C(═O)—	K008	J012	T152
282	—(CH2)2—	—NH—C(═O)—	K008	J018	T151
283	—(CH2)2—	—NH—C(═O)—	K008	J022	T148
284	—(CH2)2—	—NH—C(═O)—	K008	J022	T169
285	—(CH2)2—	—NH—C(═O)—	K008	J039	T148
286	—(CH2)2—	—NH—C(═O)—	K008	J039	T152
287	—(CH2)2—	—NH—C(═O)—	K008	J045	T148
288	—(CH2)2—	—NH—C(═O)—	K008	J045	T152
289	—(CH2)2—	—NH—C(═O)—	K008	J056	T148
290	—(CH2)2—	—NH—C(═O)—	K008	J056	T151
291	—(CH2)2—	—NH—C(═O)—	K008	J073	T148
292	—(CH2)2—	—NH—C(═O)—	K008	J073	T169
293	—(CH2)2—	—NH—C(═O)—	K009	J006	T148
294	—(CH2)2—	—NH—C(═O)—	K009	J006	T152
295	—(CH2)2—	—NH—C(═O)—	K009	J008	T148
296	—(CH2)2—	—NH—C(═O)—	K009	J009	T148
297	—(CH2)2—	—NH—C(═O)—	K009	J012	T148
298	—(CH2)2—	—NH—C(═O)—	K009	J023	T148
299	—(CH2)2—	—NH—C(═O)—	K009	J023	T151
300	—(CH2)2—	—NH—C(═O)—	K009	J040	T148
301	—(CH2)2—	—NH—C(═O)—	K009	J040	T169
302	—(CH2)2—	—NH—C(═O)—	K009	J043	T152
303	—(CH2)2—	—NH—C(═O)—	K009	J045	T148
304	—(CH2)2—	—NH—C(═O)—	K009	J057	T148
305	—(CH2)2—	—NH—C(═O)—	K009	J057	T152
306	—(CH2)2—	—NH—C(═O)—	K009	J074	T148
307	—(CH2)2—	—NH—C(═O)—	K009	J074	T151
308	—(CH2)2—	—NH—C(═O)—	K010	J045	T157
309	—(CH2)2—	—NH—C(═O)—	K011	J007	T148
310	—(CH2)2—	—NH—C(═O)—	K011	J007	T169
311	—(CH2)2—	—NH—C(═O)—	K011	J008	T148
312	—(CH2)2—	—NH—C(═O)—	K011	J009	T148
313	—(CH2)2—	—NH—C(═O)—	K011	J012	T148
314	—(CH2)2—	—NH—C(═O)—	K011	J024	T148
315	—(CH2)2—	—NH—C(═O)—	K011	J024	T152
316	—(CH2)2—	—NH—C(═O)—	K011	J041	T148
317	—(CH2)2—	—NH—C(═O)—	K011	J041	T151
318	—(CH2)2—	—NH—C(═O)—	K011	J045	T003
319	—(CH2)2—	—NH—C(═O)—	K011	J045	T004
320	—(CH2)2—	—NH—C(═O)—	K011	J045	T005
321	—(CH2)2—	—NH—C(═O)—	K011	J045	T148
322	—(CH2)2—	—NH—C(═O)—	K011	J058	T148
323	—(CH2)2—	—NH—C(═O)—	K011	J058	T169
324	—(CH2)2—	—NH—C(═O)—	K011	J063	T158
325	—(CH2)2—	—NH—C(═O)—	K011	J075	T148
326	—(CH2)2—	—NH—C(═O)—	K011	J075	T152
327	—(CH2)2—	—NH—C(═O)—	K012	J008	T148
328	—(CH2)2—	—NH—C(═O)—	K012	J008	T151
329	—(CH2)2—	—NH—C(═O)—	K012	J009	T148
330	—(CH2)2—	—NH—C(═O)—	K012	J012	T148
331	—(CH2)2—	—NH—C(═O)—	K012	J025	T148
332	—(CH2)2—	—NH—C(═O)—	K012	J025	T169
333	—(CH2)2—	—NH—C(═O)—	K012	J042	T148
334	—(CH2)2—	—NH—C(═O)—	K012	J042	T152
335	—(CH2)2—	—NH—C(═O)—	K012	J045	T148
336	—(CH2)2—	—NH—C(═O)—	K012	J059	T148
337	—(CH2)2—	—NH—C(═O)—	K012	J059	T151
338	—(CH2)2—	—NH—C(═O)—	K012	J076	T148
339	—(CH2)2—	—NH—C(═O)—	K012	J076	T169
340	—(CH2)2—	—NH—C(═O)—	K012	J081	T164
341	—(CH2)2—	—NH—C(═O)—	K013	J001	T168
342	—(CH2)2—	—NH—C(═O)—	K013	J008	T148
343	—(CH2)2—	—NH—C(═O)—	K013	J012	T148
344	—(CH2)2—	—NH—C(═O)—	K013	J045	T005
345	—(CH2)2—	—NH—C(═O)—	K013	J045	T077
346	—(CH2)2—	—NH—C(═O)—	K013	J045	T090
347	—(CH2)2—	—NH—C(═O)—	K013	J045	T129
348	—(CH2)2—	—NH—C(═O)—	K013	J045	T148
349	—(CH2)2—	—NH—C(═O)—	K014	J002	T169
350	—(CH2)2—	—NH—C(═O)—	K015	J008	T170
351	—(CH2)2—	—NH—C(═O)—	K016	J009	T173
352	—(CH2)2—	—NH—C(═O)—	K017	J012	T176
353	—(CH2)2—	—NH—C(═O)—	K018	J014	T178
354	—(CH2)2—	—NH—C(═O)—	K019	J015	T129
355	—(CH2)2—	—NH—C(═O)—	K020	J018	T130
356	—(CH2)2—	—NH—C(═O)—	K021	J043	T134
357	—(CH2)2—	—NH—C(═O)—	K022	J045	T135
358	—(CH2)2—	—NH—C(═O)—	K023	J063	T145
359	—(CH2)2—	—NH—C(═O)—	K024	J081	T148
360	—(CH2)2—	—NH—C(═O)—	K025	J001	T149
361	—(CH2)2—	—NH—C(═O)—	K025	J045	T148
362	—(CH2)2—	—NH—C(═O)—	K026	J002	T151
363	—(CH2)2—	—NH—C(═O)—	K027	J008	T152
364	—(CH2)2—	—NH—C(═O)—	K028	J009	T157
365	—(CH2)2—	—NH—C(═O)—	K029	J012	T158
366	—(CH2)2—	—NH—C(═O)—	K030	J014	T164
367	—(CH2)2—	—NH—C(═O)—	K031	J015	T168
368	—(CH2)2—	—NH—C(═O)—	K032	J018	T169
369	—(CH2)2—	—NH—C(═O)—	K033	J043	T170
370	—(CH2)2—	—NH—C(═O)—	K033	J045	T004
371	—(CH2)2—	—NH—C(═O)—	K034	J045	T173
372	—(CH2)2—	—NH—C(═O)—	K035	J063	T176
373	—(CH2)2—	—NH—C(═O)—	K036	J081	T178
374	—(CH2)2—	—NH—C(═O)—	K037	J001	T129
375	—(CH2)2—	—NH—C(═O)—	K038	J002	T130
376	—(CH2)2—	—NH—C(═O)—	K039	J008	T134
377	—(CH2)2—	—NH—C(═O)—	K040	J009	T135
378	—(CH2)2—	—NH—C(═O)—	K041	J012	T145
379	—(CH2)2—	—NH—C(═O)—	K042	J014	T148
380	—(CH2)2—	—NH—C(═O)—	K043	J015	T149
381	—(CH2)2—	—NH—C(═O)—	K044	J010	T148
382	—(CH2)2—	—NH—C(═O)—	K044	J010	T169
383	—(CH2)2—	—NH—C(═O)—	K044	J018	T151
384	—(CH2)2—	—NH—C(═O)—	K044	J027	T148
385	—(CH2)2—	—NH—C(═O)—	K044	J027	T152
386	—(CH2)2—	—NH—C(═O)—	K044	J044	T148
387	—(CH2)2—	—NH—C(═O)—	K044	J044	T151
388	—(CH2)2—	—NH—C(═O)—	K044	J061	T148
389	—(CH2)2—	—NH—C(═O)—	K044	J061	T169
390	—(CH2)2—	—NH—C(═O)—	K044	J078	T148
391	—(CH2)2—	—NH—C(═O)—	K044	J078	T152
392	—(CH2)2—	—NH—C(═O)—	K045	J043	T152
393	—(CH2)2—	—NH—C(═O)—	K046	J045	T157
394	—(CH2)2—	—NH—C(═O)—	K047	J063	T158
395	—(CH2)2—	—NH—C(═O)—	K048	J081	T164
396	—(CH2)2—	—NH—C(═O)—	K049	J001	T168
397	—(CH2)2—	—NH—C(═O)—	K050	J002	T169
398	—(CH2)2—	—NH—C(═O)—	K051	J008	T170
399	—(CH2)2—	—NH—C(═O)—	K052	J009	T173
400	—(CH2)2—	—NH—C(═O)—	K053	J012	T176
401	—(CH2)2—	—NH—C(═O)—	K054	J014	T178
402	—(CH2)2—	—NH—C(═O)—	K055	J015	T129
403	—(CH2)2—	—NH—C(═O)—	K056	J018	T130
404	—(CH2)2—	—NH—C(═O)—	K057	J043	T134
405	—(CH2)2—	—NH—C(═O)—	K058	J045	T135
406	—(CH2)2—	—NH—C(═O)—	K059	J063	T145
407	—(CH2)2—	—NH—C(═O)—	K060	J081	T148
408	—(CH2)2—	—NH—C(═O)—	K061	J001	T149
409	—(CH2)2—	—NH—C(═O)—	K062	J002	T151
410	—(CH2)2—	—NH—C(═O)—	K063	J008	T152
411	—(CH2)2—	—NH—C(═O)—	K064	J009	T157
412	—(CH2)2—	—NH—C(═O)—	K065	J012	T158
413	—(CH2)2—	—NH—C(═O)—	K066	J014	T164
414	—(CH2)2—	—NH—C(═O)—	K067	J015	T168
415	—(CH2)2—	—NH—C(═O)—	K068	J018	T169
416	—(CH2)2—	—NH—C(═O)—	K069	J043	T170
417	—(CH2)2—	—NH—C(═O)—	K070	J011	T148
418	—(CH2)2—	—NH—C(═O)—	K070	J011	T151
419	—(CH2)2—	—NH—C(═O)—	K070	J028	T148
420	—(CH2)2—	—NH—C(═O)—	K070	J028	T169
421	—(CH2)2—	—NH—C(═O)—	K070	J045	T148
422	—(CH2)2—	—NH—C(═O)—	K070	J045	T152
423	—(CH2)2—	—NH—C(═O)—	K070	J045	T173
424	—(CH2)2—	—NH—C(═O)—	K070	J062	T148
425	—(CH2)2—	—NH—C(═O)—	K070	J062	T151
426	—(CH2)2—	—NH—C(═O)—	K070	J079	T148
427	—(CH2)2—	—NH—C(═O)—	K070	J079	T169
428	—(CH2)2—	—NH—C(═O)—	K071	J063	T176
429	—(CH2)2—	—NH—C(═O)—	K072	J012	T148
430	—(CH2)2—	—NH—C(═O)—	K072	J012	T152
431	—(CH2)2—	—NH—C(═O)—	K072	J029	T148
432	—(CH2)2—	—NH—C(═O)—	K072	J029	T151
433	—(CH2)2—	—NH—C(═O)—	K072	J046	T148
434	—(CH2)2—	—NH—C(═O)—	K072	J046	T169
435	—(CH2)2—	—NH—C(═O)—	K072	J063	T148
436	—(CH2)2—	—NH—C(═O)—	K072	J063	T152
437	—(CH2)2—	—NH—C(═O)—	K072	J080	T148
438	—(CH2)2—	—NH—C(═O)—	K072	J080	T151
439	—(CH2)2—	—NH—C(═O)—	K072	J081	T178
440	—(CH2)2—	—NH—C(═O)—	K073	J001	T129
441	—(CH2)2—	—NH—C(═O)—	K074	J002	T130
442	—(CH2)2—	—NH—C(═O)—	K075	J008	T134
443	—(CH2)2—	—NH—C(═O)—	K076	J009	T135
444	—(CH2)2—	—NH—C(═O)—	K077	J012	T145
445	—(CH2)2—	—NH—C(═O)—	K078	J014	T148
446	—(CH2)2—	—NH—C(═O)—	K079	J015	T149
447	—(CH2)2—	—NH—C(═O)—	K080	J018	T151
448	—(CH2)2—	—NH—C(═O)—	K081	J043	T152
449	—(CH2)2—	—NH—C(═O)—	K082	J045	T157
450	—(CH2)2—	—NH—C(═O)—	K083	J063	T158
451	—(CH2)2—	—NH—C(═O)—	K084	J081	T164
452	—(CH2)2—	—NH—C(═O)—	K085	J001	T168
453	—(CH2)2—	—NH—C(═O)—	K086	J002	T169
454	—(CH2)2—	—NH—C(═O)—	K087	J008	T170
455	—(CH2)2—	—NH—C(═O)—	K088	J009	T173
456	—(CH2)2—	—NH—C(═O)—	K089	J012	T176
457	—(CH2)2—	—NH—C(═O)—	K090	J014	T178
458	—(CH2)2—	—NH—C(═O)—	K091	J015	T129
459	—(CH2)2—	—NH—C(═O)—	K092	J018	T130
460	—(CH2)2—	—NH—C(═O)—	K093	J043	T134
461	—(CH2)2—	—NH—C(═O)—	K094	J045	T135
462	—(CH2)2—	—NH—C(═O)—	K095	J063	T145
463	—(CH2)2—	—NH—C(═O)—	K096	J081	T148
464	—(CH2)2—	—NH—C(═O)—	K097	J001	T149
465	—(CH2)2—	—NH—C(═O)—	K098	J002	T151
466	—(CH2)2—	—NH—C(═O)—	K099	J008	T152
467	—(CH2)2—	—NH—C(═O)—	K100	J009	T157
468	—(CH2)2—	—NH—C(═O)—	K101	J012	T158
469	—(CH2)2—	—NH—C(═O)—	K102	J014	T164
470	—(CH2)2—	—NH—C(═O)—	K103	J015	T168
471	—(CH2)2—	—NH—C(═O)—	K104	J018	T169
472	—(CH2)2—	—NH—C(═O)—	K105	J043	T170
473	—(CH2)2—	—NH—C(═O)—	K106	J045	T173
474	—(CH2)2—	—NH—C(═O)—	K107	J013	T148
475	—(CH2)2—	—NH—C(═O)—	K107	J013	T169
476	—(CH2)2—	—NH—C(═O)—	K107	J030	T148
477	—(CH2)2—	—NH—C(═O)—	K107	J030	T152
478	—(CH2)2—	—NH—C(═O)—	K107	J047	T148
479	—(CH2)2—	—NH—C(═O)—	K107	J047	T151
480	—(CH2)2—	—NH—C(═O)—	K107	J063	T176
481	—(CH2)2—	—NH—C(═O)—	K107	J064	T148
482	—(CH2)2—	—NH—C(═O)—	K107	J064	T169
483	—(CH2)2—	—NH—C(═O)—	K107	J081	T148
484	—(CH2)2—	—NH—C(═O)—	K107	J081	T152
485	—(CH2)2—	—NH—C(═O)—	K108	J008	T148
486	—(CH2)2—	—NH—C(═O)—	K108	J009	T148
487	—(CH2)2—	—NH—C(═O)—	K108	J012	T148
488	—(CH2)2—	—NH—C(═O)—	K108	J014	T148
489	—(CH2)2—	—NH—C(═O)—	K108	J014	T151
490	—(CH2)2—	—NH—C(═O)—	K108	J031	T148
491	—(CH2)2—	—NH—C(═O)—	K108	J031	T169
492	—(CH2)2—	—NH—C(═O)—	K108	J045	T148
493	—(CH2)2—	—NH—C(═O)—	K108	J048	T148
494	—(CH2)2—	—NH—C(═O)—	K108	J048	T152
495	—(CH2)2—	—NH—C(═O)—	K108	J065	T148
496	—(CH2)2—	—NH—C(═O)—	K108	J065	T151
497	—(CH2)2—	—NH—C(═O)—	K108	J081	T178
498	—(CH2)2—	—NH—C(═O)—	K108	J082	T148
499	—(CH2)2—	—NH—C(═O)—	K108	J082	T169
500	—(CH2)2—	—NH—C(═O)—	K109	J001	T129
501	—(CH2)2—	—NH—C(═O)—	K109	J008	T148
502	—(CH2)2—	—NH—C(═O)—	K109	J009	T148
503	—(CH2)2—	—NH—C(═O)—	K109	J012	T148
504	—(CH2)2—	—NH—C(═O)—	K109	J045	T148
505	—(CH2)2—	—NH—C(═O)—	K110	J002	T130
506	—(CH2)2—	—NH—C(═O)—	K111	J008	T134
507	—(CH2)2—	—NH—C(═O)—	K112	J009	T135
508	—(CH2)2—	—NH—C(═O)—	K113	J012	T145
509	—(CH2)2—	—NH—C(═O)—	K114	J014	T148
510	—(CH2)2—	—NH—C(═O)—	K115	J015	T149
511	—(CH2)2—	—NH—C(═O)—	K116	J018	T151
512	—(CH2)2—	—NH—C(═O)—	K117	J043	T152
513	—(CH2)2—	—NH—C(═O)—	K118	J045	T157
514	—(CH2)2—	—NH—C(═O)—	K119	J063	T158
515	—(CH2)2—	—NH—C(═O)—	K120	J081	T164
516	—(CH2)2—	—NH—C(═O)—	K121	J001	T168
517	—(CH2)2—	—NH—C(═O)—	K122	J002	T169
518	—(CH2)2—	—NH—C(═O)—	K123	J008	T170
519	—(CH2)2—	—NH—C(═O)—	K124	J009	T173
520	—(CH2)2—	—NH—C(═O)—	K125	J012	T176
521	—(CH2)2—	—NH—C(═O)—	K126	J014	T178
522	—(CH2)2—	—NH—C(═O)—	K127	J015	T129
523	—(CH2)2—	—NH—C(═O)—	K128	J018	T130
524	—(CH2)2—	—NH—C(═O)—	K129	J043	T134
525	—(CH2)2—	—NH—C(═O)—	K130	J045	T135
526	—(CH2)2—	—NH—C(═O)—	K131	J063	T145
527	—(CH2)2—	—NH—C(═O)—	K132	J081	T148
528	—(CH2)2—	—NH—C(═O)—	K133	J001	T149
529	—(CH2)2—	—NH—C(═O)—	K134	J002	T151
530	—(CH2)2—	—NH—C(═O)—	K135	J008	T152
531	—(CH2)2—	—NH—C(═O)—	K136	J009	T157
532	—(CH2)2—	—NH—C(═O)—	K137	J008	T148
533	—(CH2)2—	—NH—C(═O)—	K137	J009	T148
534	—(CH2)2—	—NH—C(═O)—	K137	J012	T148
535	—(CH2)2—	—NH—C(═O)—	K137	J012	T158
536	—(CH2)2—	—NH—C(═O)—	K137	J045	T148
537	—(CH2)2—	—NH—C(═O)—	K138	J014	T164
538	—(CH2)2—	—NH—C(═O)—	K139	J015	T168
539	—(CH2)2—	—NH—C(═O)—	K140	J018	T169
540	—(CH2)2—	—NH—C(═O)—	K141	J043	T170
541	—(CH2)2—	—NH—C(═O)—	K142	J045	T173
542	—(CH2)2—	—NH—C(═O)—	K143	J063	T176
543	—(CH2)2—	—NH—C(═O)—	K144	J008	T148
544	—(CH2)2—	—NH—C(═O)—	K144	J009	T148
545	—(CH2)2—	—NH—C(═O)—	K144	J012	T148
546	—(CH2)2—	—NH—C(═O)—	K144	J015	T148
547	—(CH2)2—	—NH—C(═O)—	K144	J015	T152
548	—(CH2)2—	—NH—C(═O)—	K144	J032	T148
549	—(CH2)2—	—NH—C(═O)—	K144	J032	T151
550	—(CH2)2—	—NH—C(═O)—	K144	J045	T148
551	—(CH2)2—	—NH—C(═O)—	K144	J049	T148
552	—(CH2)2—	—NH—C(═O)—	K144	J049	T169
553	—(CH2)2—	—NH—C(═O)—	K144	J066	T148
554	—(CH2)2—	—NH—C(═O)—	K144	J066	T152
555	—(CH2)2—	—NH—C(═O)—	K144	J081	T178
556	—(CH2)2—	—NH—C(═O)—	K144	J083	T148
557	—(CH2)2—	—NH—C(═O)—	K144	J083	T151
558	—(CH2)2—	—NH—C(═O)—	K145	J001	T129
559	—(CH2)2—	—NH—C(═O)—	K146	J002	T130
560	—(CH2)2—	—NH—C(═O)—	K147	J008	T134
561	—(CH2)2—	—NH—C(═O)—	K148	J009	T135
562	—(CH2)2—	—NH—C(═O)—	K149	J012	T145
563	—(CH2)2—	—NH—C(═O)—	K150	J014	T148
564	—(CH2)2—	—NH—C(═O)—	K151	J015	T149
565	—(CH2)2—	—NH—C(═O)—	K152	J018	T151
566	—(CH2)2—	—NH—C(═O)—	K153	J043	T152
567	—(CH2)2—	—NH—C(═O)—	K154	J045	T157
568	—(CH2)2—	—NH—C(═O)—	K155	J063	T158
569	—(CH2)2—	—NH—C(═O)—	K156	J081	T164
570	—(CH2)2—	—NH—C(═O)—	K157	J001	T168
571	—(CH2)2—	—NH—C(═O)—	K158	J002	T169
572	—(CH2)2—	—NH—C(═O)—	K159	J008	T170
573	—(CH2)2—	—NH—C(═O)—	K160	J009	T173
574	—(CH2)2—	—NH—C(═O)—	K161	J012	T176
575	—(CH2)2—	—NH—C(═O)—	K162	J014	T178
576	—(CH2)2—	—NH—C(═O)—	K163	J015	T129
577	—(CH2)2—	—NH—C(═O)—	K164	J018	T130
578	—(CH2)2—	—NH—C(═O)—	K165	J043	T134
579	—(CH2)2—	—NH—C(═O)—	K166	J045	T135
580	—(CH2)2—	—NH—C(═O)—	K167	J063	T145
581	—(CH2)2—	—NH—C(═O)—	K168	J081	T148
582	—(CH2)2—	—NH—C(═O)—	K169	J001	T149
583	—(CH2)2—	—NH—C(═O)—	K170	J002	T151
584	—(CH2)2—	—NH—C(═O)—	K171	J008	T152
585	—(CH2)2—	—NH—C(═O)—	K172	J009	T157
586	—(CH2)2—	—NH—C(═O)—	K173	J012	T158
587	—(CH2)2—	—NH—C(═O)—	K174	J014	T164
588	—(CH2)2—	—NH—C(═O)—	K175	J015	T168
589	—(CH2)2—	—NH—C(═O)—	K176	J018	T169
590	—(CH2)2—	—NH—C(═O)—	K177	J043	T170
591	—(CH2)2—	—NH—C(═O)—	K178	J045	T173
592	—(CH2)2—	—NH—C(═O)—	K197	J063	T176
593	—(CH2)2—	—NH—C(═O)—	K198	J008	T148
594	—(CH2)2—	—NH—C(═O)—	K198	J009	T148
595	—(CH2)2—	—NH—C(═O)—	K198	J012	T148
596	—(CH2)2—	—NH—C(═O)—	K198	J045	T148
597	—(CH2)2—	—NH—C(═O)—	K198	J081	T178
598	—(CH2)2—	—NH—C(═O)—	K199	J001	T129
599	—(CH2)2—	—NH—C(═O)—	K199	J008	T148
600	—(CH2)2—	—NH—C(═O)—	K199	J009	T148
601	—(CH2)2—	—NH—C(═O)—	K199	J012	T148
602	—(CH2)2—	—NH—C(═O)—	K199	J045	T148
603	—(CH2)2—	—NH—C(═O)—	K200	J002	T130
604	—(CH2)2—	—NH—C(═O)—	K200	J008	T005
605	—(CH2)2—	—NH—C(═O)—	K200	J008	T148
606	—(CH2)2—	—NH—C(═O)—	K200	J008	T151
607	—(CH2)2—	—NH—C(═O)—	K200	J008	T152
608	—(CH2)2—	—NH—C(═O)—	K200	J008	T169
609	—(CH2)2—	—NH—C(═O)—	K200	J009	T005
610	—(CH2)2—	—NH—C(═O)—	K200	J009	T148
611	—(CH2)2—	—NH—C(═O)—	K200	J009	T151
612	—(CH2)2—	—NH—C(═O)—	K200	J009	T152
613	—(CH2)2—	—NH—C(═O)—	K200	J009	T169
614	—(CH2)2—	—NH—C(═O)—	K200	J012	T005
615	—(CH2)2—	—NH—C(═O)—	K200	J012	T148
616	—(CH2)2—	—NH—C(═O)—	K200	J012	T151
617	—(CH2)2—	—NH—C(═O)—	K200	J012	T152
618	—(CH2)2—	—NH—C(═O)—	K200	J012	T169
619	—(CH2)2—	—NH—C(═O)—	K200	J016	T005
620	—(CH2)2—	—NH—C(═O)—	K200	J016	T148
621	—(CH2)2—	—NH—C(═O)—	K200	J016	T169
622	—(CH2)2—	—NH—C(═O)—	K200	J033	T005
623	—(CH2)2—	—NH—C(═O)—	K200	J033	T148
624	—(CH2)2—	—NH—C(═O)—	K200	J033	T152
625	—(CH2)2—	—NH—C(═O)—	K200	J045	T005
626	—(CH2)2—	—NH—C(═O)—	K200	J045	T148
627	—(CH2)2—	—NH—C(═O)—	K200	J045	T151
628	—(CH2)2—	—NH—C(═O)—	K200	J045	T152
629	—(CH2)2—	—NH—C(═O)—	K200	J045	T169
630	—(CH2)2—	—NH—C(═O)—	K200	J050	T148
631	—(CH2)2—	—NH—C(═O)—	K200	J050	T151
632	—(CH2)2—	—NH—C(═O)—	K200	J067	T148
633	—(CH2)2—	—NH—C(═O)—	K200	J067	T169
634	—(CH2)2—	—NH—C(═O)—	K200	J084	T148
635	—(CH2)2—	—NH—C(═O)—	K200	J084	T152
636	—(CH2)2—	—NH—C(═O)—	K201	J008	T134
637	—(CH2)2—	—NH—C(═O)—	K202	J009	T135
638	—(CH2)2—	—NH—C(═O)—	K203	J008	T148
639	—(CH2)2—	—NH—C(═O)—	K203	J009	T148
640	—(CH2)2—	—NH—C(═O)—	K203	J012	T145
641	—(CH2)2—	—NH—C(═O)—	K203	J012	T148
642	—(CH2)2—	—NH—C(═O)—	K203	J017	T148
643	—(CH2)2—	—NH—C(═O)—	K203	J017	T151
644	—(CH2)2—	—NH—C(═O)—	K203	J034	T148
645	—(CH2)2—	—NH—C(═O)—	K203	J034	T169
646	—(CH2)2—	—NH—C(═O)—	K203	J045	T148
647	—(CH2)2—	—NH—C(═O)—	K203	J051	T148
648	—(CH2)2—	—NH—C(═O)—	K203	J051	T152
649	—(CH2)2—	—NH—C(═O)—	K203	J068	T148
650	—(CH2)2—	—NH—C(═O)—	K203	J068	T151
651	—(CH2)2—	—NH—C(═O)—	K203	J085	T148
652	—(CH2)2—	—NH—C(═O)—	K203	J085	T169
653	—(CH2)2—	—NH—C(═O)—	K204	J014	T148
654	—(CH2)2—	—NH—C(═O)—	K205	J015	T149
655	—(CH2)2—	—NH—C(═O)—	K206	J008	T148
656	—(CH2)2—	—NH—C(═O)—	K206	J009	T148
657	—(CH2)2—	—NH—C(═O)—	K206	J012	T148
658	—(CH2)2—	—NH—C(═O)—	K206	J018	T151
659	—(CH2)2—	—NH—C(═O)—	K206	J045	T148
660	—(CH2)2—	—NH—C(═O)—	K207	J008	T148
661	—(CH2)2—	—NH—C(═O)—	K207	J009	T148
662	—(CH2)2—	—NH—C(═O)—	K207	J012	T148
663	—(CH2)2—	—NH—C(═O)—	K207	J043	T152
664	—(CH2)2—	—NH—C(═O)—	K207	J045	T148
665	—(CH2)2—	—NH—C(═O)—	K208	J008	T148
666	—(CH2)2—	—NH—C(═O)—	K208	J009	T148
667	—(CH2)2—	—NH—C(═O)—	K208	J012	T148
668	—(CH2)2—	—NH—C(═O)—	K208	J045	T148
669	—(CH2)2—	—NH—C(═O)—	K208	J045	T157
670	—(CH2)2—	—NH—C(═O)—	K209	J008	T148
671	—(CH2)2—	—NH—C(═O)—	K209	J009	T148
672	—(CH2)2—	—NH—C(═O)—	K209	J012	T148
673	—(CH2)2—	—NH—C(═O)—	K209	J045	T148
674	—(CH2)2—	—NH—C(═O)—	K209	J063	T158
675	—(CH2)2—	—NH—C(═O)—	K210	J008	T148
676	—(CH2)2—	—NH—C(═O)—	K210	J009	T148
677	—(CH2)2—	—NH—C(═O)—	K270	J012	T148
678	—(CH2)2—	—NH—C(═O)—	K210	J045	T148
679	—(CH2)2—	—NH—C(═O)—	K210	J081	T164
680	—(CH2)2—	—NH—C(═O)—	K211	J001	T168
681	—(CH2)2—	—NH—C(═O)—	K211	J008	T148
682	—(CH2)2—	—NH—C(═O)—	K211	J009	T148
683	—(CH2)2—	—NH—C(═O)—	K211	J012	T148
684	—(CH2)2—	—NH—C(═O)—	K211	J045	T148
685	—(CH2)2—	—NH—C(═O)—	K212	J002	T169
686	—(CH2)2—	—NH—C(═O)—	K212	J008	T148
687	—(CH2)2—	—NH—C(═O)—	K212	J009	T148
688	—(CH2)2—	—NH—C(═O)—	K212	J012	T148
689	—(CH2)2—	—NH—C(═O)—	K212	J045	T148
690	—(CH2)2—	—NH—C(═O)—	K213	J008	T170
691	—(CH2)2—	—NH—C(═O)—	K214	J009	T173
692	—(CH2)2—	—NH—C(═O)—	K215	J008	T148
693	—(CH2)2—	—NH—C(═O)—	K215	J009	T148
694	—(CH2)2—	—NH—C(═O)—	K215	J012	T148
695	—(CH2)2—	—NH—C(═O)—	K215	J012	T176
696	—(CH2)2—	—NH—C(═O)—	K215	J045	T148
697	—(CH2)2—	—NH—C(═O)—	K216	J014	T178
698	—(CH2)2—	—NH—C(═O)—	K217	J015	T129
699	—(CH2)2—	—NH—C(═O)—	K218	J018	T130
700	—(CH2)2—	—NH—C(═O)—	K219	J008	T148
701	—(CH2)2—	—NH—C(═O)—	K219	J009	T148
702	—(CH2)2—	—NH—C(═O)—	K219	J012	T148
703	—(CH2)2—	—NH—C(═O)—	K219	J043	T134
704	—(CH2)2—	—NH—C(═O)—	K219	J045	T148
705	—(CH2)2—	—NH—C(═O)—	K220	J008	T148
706	—(CH2)2—	—NH—C(═O)—	K220	J009	T148
707	—(CH2)2—	—NH—C(═O)—	K220	J012	T148
708	—(CH2)2—	—NH—C(═O)—	K220	J045	T135
709	—(CH2)2—	—NH—C(═O)—	K220	J045	T148
710	—(CH2)2—	—NH—C(═O)—	K221	J008	T148
711	—(CH2)2—	—NH—C(═O)—	K221	J009	T148
712	—(CH2)2—	—NH—C(═O)—	K221	J012	T148
713	—(CH2)2—	—NH—C(═O)—	K221	J045	T148
714	—(CH2)2—	—NH—C(═O)—	K221	J063	T145
715	—(CH2)2—	—NH—C(═O)—	K222	J008	T148
716	—(CH2)2—	—NH—C(═O)—	K222	J009	T148
717	—(CH2)2—	—NH—C(═O)—	K222	J012	T148
718	—(CH2)2—	—NH—C(═O)—	K222	J045	T148
719	—(CH2)2—	—NH—C(═O)—	K222	J081	T148
720	—(CH2)2—	—NH—C(═O)—	K223	J001	T149
721	—(CH2)2—	—NH—C(═O)—	K223	J008	T148
722	—(CH2)2—	—NH—C(═O)—	K223	J009	T148
723	—(CH2)2—	—NH—C(═O)—	K223	J012	T148
724	—(CH2)2—	—NH—C(═O)—	K223	J045	T148
725	—(CH2)2—	—NH—C(═O)—	K224	J002	T151
726	—(CH2)2—	—NH—C(═O)—	K224	J008	T148
727	—(CH2)2—	—NH—C(═O)—	K224	J009	T148
728	—(CH2)2—	—NH—C(═O)—	K224	J012	T148
729	—(CH2)2—	—NH—C(═O)—	K224	J045	T148
730	—(CH2)2—	—NH—C(═O)—	K225	J008	T148
731	—(CH2)2—	—NH—C(═O)—	K225	J008	T152
732	—(CH2)2—	—NH—C(═O)—	K225	J009	T148
733	—(CH2)2—	—NH—C(═O)—	K225	J012	T148
734	—(CH2)2—	—NH—C(═O)—	K225	J045	T148
735	—(CH2)2—	—NH—C(═O)—	K226	J009	T157
736	—(CH2)2—	—NH—C(═O)—	K227	J012	T158
737	—(CH2)2—	—NH—C(═O)—	K228	J008	T148
738	—(CH2)2—	—NH—C(═O)—	K228	J009	T148
739	—(CH2)2—	—NH—C(═O)—	K228	J012	T148
740	—(CH2)2—	—NH—C(═O)—	K228	J014	T164
741	—(CH2)2—	—NH—C(═O)—	K228	J045	T148
742	—(CH2)2—	—NH—C(═O)—	K229	J015	T168
743	—(CH2)2—	—NH—C(═O)—	K230	J018	T169
744	—(CH2)2—	—NH—C(═O)—	K231	J043	T170
745	—(CH2)2—	—NH—C(═O)—	K232	J045	T173
746	—(CH2)2—	—NH—C(═O)—	K233	J063	T176
747	—(CH2)2—	—NH—C(═O)—	K234	J081	T178
748	—(CH2)2—	—NH—C(═O)—	K235	J012	T148
749	—(CH2)2—	—NH—C(═O)—	K236	J045	T148
750	—(CH2)2—	—NH—C(═O)—NH—	K003	J002	T148
751	—(CH2)2—	—NH—C(═O)—NH—	K003	J002	T151
752	—(CH2)2—	—NH—C(═O)—NH—	K003	J008	T148
753	—(CH2)2—	—NH—C(═O)—NH—	K003	J008	T151
754	—(CH2)2—	—NH—C(═O)—NH—	K003	J008	T152
755	—(CH2)2—	—NH—C(═O)—NH—	K003	J008	T169
756	—(CH2)2—	—NH—C(═O)—NH—	K003	J009	T148
757	—(CH2)2—	—NH—C(═O)—NH—	K003	J009	T151
758	—(CH2)2—	—NH—C(═O)—NH—	K003	J009	T152
759	—(CH2)2—	—NH—C(═O)—NH—	K003	J009	T169
760	—(CH2)2—	—NH—C(═O)—NH—	K003	J012	T148
761	—(CH2)2—	—NH—C(═O)—NH—	K003	J012	T151
762	—(CH2)2—	—NH—C(═O)—NH—	K003	J012	T152
763	—(CH2)2—	—NH—C(═O)—NH—	K003	J012	T169
764	—(CH2)2—	—NH—C(═O)—NH—	K003	J019	T148
765	—(CH2)2—	—NH—C(═O)—NH—	K003	J019	T169
766	—(CH2)2—	—NH—C(═O)—NH—	K003	J036	T148
767	—(CH2)2—	—NH—C(═O)—NH—	K003	J036	T152
768	—(CH2)2—	—NH—C(═O)—NH—	K003	J045	T148
769	—(CH2)2—	—NH—C(═O)—NH—	K003	J045	T151
770	—(CH2)2—	—NH—C(═O)—NH—	K003	J045	T152
771	—(CH2)2—	—NH—C(═O)—NH—	K003	J045	T169
772	—(CH2)2—	—NH—C(═O)—NH—	K003	J053	T148
773	—(CH2)2—	—NH—C(═O)—NH—	K003	J053	T151
774	—(CH2)2—	—NH—C(═O)—NH—	K003	J070	T148
775	—(CH2)2—	—NH—C(═O)—NH—	K003	J070	T169
776	—(CH2)2—	—NH—C(═O)—NH—	K009	J045	T148
777	—(CH2)2—	—NH—C(═O)—NH—	K012	J008	T148
778	—(CH2)2—	—NH—C(═O)—NH—	K012	J008	T151
779	—(CH2)2—	—NH—C(═O)—NH—	K012	J008	T152
780	—(CH2)2—	—NH—C(═O)—NH—	K012	J008	T169
781	—(CH2)2—	—NH—C(═O)—NH—	K012	J009	T148
782	—(CH2)2—	—NH—C(═O)—NH—	K012	J009	T151
783	—(CH2)2—	—NH—C(═O)—NH—	K012	J009	T152
784	—(CH2)2—	—NH—C(═O)—NH—	K012	J009	T169
785	—(CH2)2—	—NH—C(═O)—NH—	K012	J012	T148
786	—(CH2)2—	—NH—C(═O)—NH—	K012	J012	T151
787	—(CH2)2—	—NH—C(═O)—NH—	K012	J012	T152
788	—(CH2)2—	—NH—C(═O)—NH—	K012	J012	T169
789	—(CH2)2—	—NH—C(═O)—NH—	K012	J026	T148
790	—(CH2)2—	—NH—C(═O)—NH—	K012	J026	T151
791	—(CH2)2—	—NH—C(═O)—NH—	K012	J043	T148
792	—(CH2)2—	—NH—C(═O)—NH—	K012	J043	T169
793	—(CH2)2—	—NH—C(═O)—NH—	K012	J045	T148
794	—(CH2)2—	—NH—C(═O)—NH—	K012	J045	T151
795	—(CH2)2—	—NH—C(═O)—NH—	K012	J045	T152
796	—(CH2)2—	—NH—C(═O)—NH—	K012	J045	T169
797	—(CH2)2—	—NH—C(═O)—NH—	K012	J060	T148
798	—(CH2)2—	—NH—C(═O)—NH—	K012	J060	T152
799	—(CH2)2—	—NH—C(═O)—NH—	K012	J077	T148
800	—(CH2)2—	—NH—C(═O)—NH—	K012	J077	T151
801	—(CH2)2—	—NH—C(═O)—NH—	K013	J045	T148
802	—(CH2)2—	—NH—C(═O)—NH—	K014	J045	T148
803	—(CH2)2—	—NH—C(═O)—NH—	K017	J045	T148
804	—(CH2)2—	—NH—C(═O)—NH—	K032	J045	T148
805	—(CH2)2—	—NH—C(═O)—NH—	K229	J045	T148
806	—(CH2)2—	—NH—C(═O)—NH—	K230	J045	T148
807	—(CH2)2—	—NH—C(═O)—NH—	K231	J045	T148
808	—(CH2)2—	—NH—C(═O)—NH—	K232	J045	T148
809	—(CH2)2—	—NH—C(═O)—NH—	K233	J045	T148
810	—(CH2)2—	—NH—C(═O)—NH—	K234	J045	T148
811	—(CH2)2—	—NH—C(═O)—NH—	K235	J045	T148
812	—(CH2)2—	—NH—C(═O)—NH—	K236	J045	T148
813	—(CH2)2—	—NH—C(═O)—O—	K005	J001	T001
814	—(CH2)2—	—NH—C(═O)—O—	K005	J001	T005
815	—(CH2)2—	—NH—C(═O)—O—	K005	J001	T010
816	—(CH2)2—	—NH—C(═O)—O—	K005	J001	T019
817	—(CH2)2—	—NH—C(═O)—O—	K005	J001	T028
818	—(CH2)2—	—NH—C(═O)—O—	K005	J001	T037
819	—(CH2)2—	—NH—C(═O)—O—	K005	J001	T046
820	—(CH2)2—	—NH—C(═O)—O—	K005	J001	T055
821	—(CH2)2—	—NH—C(═O)—O—	K005	J001	T064
822	—(CH2)2—	—NH—C(═O)—O—	K005	J001	T073
823	—(CH2)2—	—NH—C(═O)—O—	K005	J001	T082
824	—(CH2)2—	—NH—C(═O)—O—	K005	J001	T091
825	—(CH2)2—	—NH—C(═O)—O—	K005	J001	T100
826	—(CH2)2—	—NH—C(═O)—O—	K005	J001	T109
827	—(CH2)2—	—NH—C(═O)—O—	K005	J001	T118
828	—(CH2)2—	—NH—C(═O)—O—	K005	J001	T127
829	—(CH2)2—	—NH—C(═O)—O—	K005	J001	T136
830	—(CH2)2—	—NH—C(═O)—O—	K005	J001	T145
831	—(CH2)2—	—NH—C(═O)—O—	K005	J001	T154
832	—(CH2)2—	—NH—C(═O)—O—	K005	J001	T163
833	—(CH2)2—	—NH—C(═O)—O—	K005	J001	T172
834	—(CH2)2—	—NH—C(═O)—O—	K005	J002	T002
835	—(CH2)2—	—NH—C(═O)—O—	K005	J002	T011
836	—(CH2)2—	—NH—C(═O)—O—	K005	J002	T020
837	—(CH2)2—	—NH—C(═O)—O—	K005	J002	T029
838	—(CH2)2—	—NH—C(═O)—O—	K005	J002	T038
839	—(CH2)2—	—NH—C(═O)—O—	K005	J002	T047
840	—(CH2)2—	—NH—C(═O)—O—	K005	J002	T056
841	—(CH2)2—	—NH—C(═O)—O—	K005	J002	T065
842	—(CH2)2—	—NH—C(═O)—O—	K005	J002	T074
843	—(CH2)2—	—NH—C(═O)—O—	K005	J002	T083
844	—(CH2)2—	—NH—C(═O)—O—	K005	J002	T092
845	—(CH2)2—	—NH—C(═O)—O—	K005	J002	T101
846	—(CH2)2—	—NH—C(═O)—O—	K005	J002	T110
847	—(CH2)2—	—NH—C(═O)—O—	K005	J002	T119
848	—(CH2)2—	—NH—C(═O)—O—	K005	J002	T128
849	—(CH2)2—	—NH—C(═O)—O—	K005	J002	T137
850	—(CH2)2—	—NH—C(═O)—O—	K005	J002	T146
851	—(CH2)2—	—NH—C(═O)—O—	K005	J002	T155
852	—(CH2)2—	—NH—C(═O)—O—	K005	J002	T164
853	—(CH2)2—	—NH—C(═O)—O—	K005	J002	T173
854	—(CH2)2—	—NH—C(═O)—O—	K005	J008	T003
855	—(CH2)2—	—NH—C(═O)—O—	K005	J008	T005
856	—(CH2)2—	—NH—C(═O)—O—	K005	J008	T012
857	—(CH2)2—	—NH—C(═O)—O—	K005	J008	T021
858	—(CH2)2—	—NH—C(═O)—O—	K005	J008	T030
859	—(CH2)2—	—NH—C(═O)—O—	K005	J008	T039
860	—(CH2)2—	—NH—C(═O)—O—	K005	J008	T048
861	—(CH2)2—	—NH—C(═O)—O—	K005	J008	T057
862	—(CH2)2—	—NH—C(═O)—O—	K005	J008	T066
863	—(CH2)2—	—NH—C(═O)—O—	K005	J008	T075
864	—(CH2)2—	—NH—C(═O)—O—	K005	J008	T084
865	—(CH2)2—	—NH—C(═O)—O—	K005	J008	T093
866	—(CH2)2—	—NH—C(═O)—O—	K005	J008	T102
867	—(CH2)2—	—NH—C(═O)—O—	K005	J008	T111
868	—(CH2)2—	—NH—C(═O)—O—	K005	J008	T120
869	—(CH2)2—	—NH—C(═O)—O—	K005	J008	T129
870	—(CH2)2—	—NH—C(═O)—O—	K005	J008	T138
871	—(CH2)2—	—NH—C(═O)—O—	K005	J008	T147
872	—(CH2)2—	—NH—C(═O)—O—	K005	J008	T156
873	—(CH2)2—	—NH—C(═O)—O—	K005	J008	T165
874	—(CH2)2—	—NH—C(═O)—O—	K005	J008	T174
875	—(CH2)2—	—NH—C(═O)—O—	K005	J009	T004
876	—(CH2)2—	—NH—C(═O)—O—	K005	J009	T005
877	—(CH2)2—	—NH—C(═O)—O—	K005	J009	T013
878	—(CH2)2—	—NH—C(═O)—O—	K005	J009	T022
879	—(CH2)2—	—NH—C(═O)—O—	K005	J009	T031
880	—(CH2)2—	—NH—C(═O)—O—	K005	J009	T040
881	—(CH2)2—	—NH—C(═O)—O—	K005	J009	T049
882	—(CH2)2—	—NH—C(═O)—O—	K005	J009	T058
883	—(CH2)2—	—NH—C(═O)—O—	K005	J009	T067
884	—(CH2)2—	—NH—C(═O)—O—	K005	J009	T076
885	—(CH2)2—	—NH—C(═O)—O—	K005	J009	T085
886	—(CH2)2—	—NH—C(═O)—O—	K005	J009	T094
887	—(CH2)2—	—NH—C(═O)—O—	K005	J009	T103
888	—(CH2)2—	—NH—C(═O)—O—	K005	J009	T112
889	—(CH2)2—	—NH—C(═O)—O—	K005	J009	T121
890	—(CH2)2—	—NH—C(═O)—O—	K005	J009	T130
891	—(CH2)2—	—NH—C(═O)—O—	K005	J009	T139
892	—(CH2)2—	—NH—C(═O)—O—	K005	J009	T148
893	—(CH2)2—	—NH—C(═O)—O—	K005	J009	T157
894	—(CH2)2—	—NH—C(═O)—O—	K005	J009	T166
895	—(CH2)2—	—NH—C(═O)—O—	K005	J009	T175
896	—(CH2)2—	—NH—C(═O)—O—	K005	J012	T005
897	—(CH2)2—	—NH—C(═O)—O—	K005	J012	T014
898	—(CH2)2—	—NH—C(═O)—O—	K005	J012	T017
899	—(CH2)2—	—NH—C(═O)—O—	K005	J012	T023
900	—(CH2)2—	—NH—C(═O)—O—	K005	J012	T032
901	—(CH2)2—	—NH—C(═O)—O—	K005	J012	T041
902	—(CH2)2—	—NH—C(═O)—O—	K005	J012	T050
903	—(CH2)2—	—NH—C(═O)—O—	K005	J012	T055
904	—(CH2)2—	—NH—C(═O)—O—	K005	J012	T059
905	—(CH2)2—	—NH—C(═O)—O—	K005	J012	T068
906	—(CH2)2—	—NH—C(═O)—O—	K005	J012	T077
907	—(CH2)2—	—NH—C(═O)—O—	K005	J012	T086
908	—(CH2)2—	—NH—C(═O)—O—	K005	J012	T095
909	—(CH2)2—	—NH—C(═O)—O—	K005	J012	T104
910	—(CH2)2—	—NH—C(═O)—O—	K005	J012	T113
911	—(CH2)2—	—NH—C(═O)—O—	K005	J012	T122
912	—(CH2)2—	—NH—C(═O)—O—	K005	J012	T129
913	—(CH2)2—	—NH—C(═O)—O—	K005	J012	T131
914	—(CH2)2—	—NH—C(═O)—O—	K005	J012	T140
915	—(CH2)2—	—NH—C(═O)—O—	K005	J012	T148
916	—(CH2)2—	—NH—C(═O)—O—	K005	J012	T149
917	—(CH2)2—	—NH—C(═O)—O—	K005	J012	T151
918	—(CH2)2—	—NH—C(═O)—O—	K005	J012	T152
919	—(CH2)2—	—NH—C(═O)—O—	K005	J012	T158
920	—(CH2)2—	—NH—C(═O)—O—	K005	J012	T167
921	—(CH2)2—	—NH—C(═O)—O—	K005	J012	T176
922	—(CH2)2—	—NH—C(═O)—O—	K005	J043	T005
923	—(CH2)2—	—NH—C(═O)—O—	K005	J043	T006
924	—(CH2)2—	—NH—C(═O)—O—	K005	J043	T015
925	—(CH2)2—	—NH—C(═O)—O—	K005	J043	T024
926	—(CH2)2—	—NH—C(═O)—O—	K005	J043	T033
927	—(CH2)2—	—NH—C(═O)—O—	K005	J043	T042
928	—(CH2)2—	—NH—C(═O)—O—	K005	J043	T051
929	—(CH2)2—	—NH—C(═O)—O—	K005	J043	T060
930	—(CH2)2—	—NH—C(═O)—O—	K005	J043	T069
931	—(CH2)2—	—NH—C(═O)—O—	K005	J043	T078
932	—(CH2)2—	—NH—C(═O)—O—	K005	J043	T087
933	—(CH2)2—	—NH—C(═O)—O—	K005	J043	T096
934	—(CH2)2—	—NH—C(═O)—O—	K005	J043	T105
935	—(CH2)2—	—NH—C(═O)—O—	K005	J043	T114
936	—(CH2)2—	—NH—C(═O)—O—	K005	J043	T123
937	—(CH2)2—	—NH—C(═O)—O—	K005	J043	T132
938	—(CH2)2—	—NH—C(═O)—O—	K005	J043	T141
939	—(CH2)2—	—NH—C(═O)—O—	K005	J043	T150
940	—(CH2)2—	—NH—C(═O)—O—	K005	J043	T159
941	—(CH2)2—	—NH—C(═O)—O—	K005	J043	T168
942	—(CH2)2—	—NH—C(═O)—O—	K005	J043	T177
943	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T001
944	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T003
945	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T004
946	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T005
947	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T007
948	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T008
949	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T016
950	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T017
951	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T018
952	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T019
953	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T020
954	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T025
955	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T034
956	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T042
957	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T043
958	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T052
959	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T055
960	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T061
961	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T070
962	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T077
963	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T079
964	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T088
965	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T090
966	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T096
967	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T097
968	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T100
969	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T106
970	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T108
971	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T110
972	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T111
973	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T114
974	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T115
975	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T116
976	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T118
977	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T119
978	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T121
979	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T122
980	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T123
981	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T124
982	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T128
983	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T129
984	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T130
985	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T133
986	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T136
987	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T137
988	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T138
989	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T139
990	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T140
991	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T141
992	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T142
993	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T143
994	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T144
995	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T145
996	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T146
997	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T147
998	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T148
999	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T149
1000	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T150
1001	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T151
1002	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T152
1003	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T153
1004	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T154
1005	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T155
1006	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T156
1007	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T157
1008	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T158
1009	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T159
1010	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T160
1011	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T162
1012	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T163
1013	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T167
1014	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T169
1015	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T178
1016	—(CH2)2—	—NH—C(═O)—O—	K005	J063	T008
1017	—(CH2)2—	—NH—C(═O)—O—	K005	J063	T017
1018	—(CH2)2—	—NH—C(═O)—O—	K005	J063	T026
1019	—(CH2)2—	—NH—C(═O)—O—	K005	J063	T035
1020	—(CH2)2—	—NH—C(═O)—O—	K005	J063	T044
1021	—(CH2)2—	—NH—C(═O)—O—	K005	J063	T053
1022	—(CH2)2—	—NH—C(═O)—O—	K005	J063	T062
1023	—(CH2)2—	—NH—C(═O)—O—	K005	J063	T071
1024	—(CH2)2—	—NH—C(═O)—O—	K005	J063	T080
1025	—(CH2)2—	—NH—C(═O)—O—	K005	J063	T089
1026	—(CH2)2—	—NH—C(═O)—O—	K005	J063	T098
1027	—(CH2)2—	—NH—C(═O)—O—	K005	J063	T107
1028	—(CH2)2—	—NH—C(═O)—O—	K005	J063	T116
1029	—(CH2)2—	—NH—C(═O)—O—	K005	J063	T125
1030	—(CH2)2—	—NH—C(═O)—O—	K005	J063	T134
1031	—(CH2)2—	—NH—C(═O)—O—	K005	J063	T143
1032	—(CH2)2—	—NH—C(═O)—O—	K005	J063	T152
1033	—(CH2)2—	—NH—C(═O)—O—	K005	J063	T161
1034	—(CH2)2—	—NH—C(═O)—O—	K005	J063	T170
1035	—(CH2)2—	—NH—C(═O)—O—	K005	J063	T179
1036	—(CH2)2—	—NH—C(═O)—O—	K005	J081	T009
1037	—(CH2)2—	—NH—C(═O)—O—	K005	J081	T018
1038	—(CH2)2—	—NH—C(═O)—O—	K005	J081	T027
1039	—(CH2)2—	—NH—C(═O)—O—	K005	J081	T036
1040	—(CH2)2—	—NH—C(═O)—O—	K005	J081	T045
1041	—(CH2)2—	—NH—C(═O)—O—	K005	J081	T054
1042	—(CH2)2—	—NH—C(═O)—O—	K005	J081	T063
1043	—(CH2)2—	—NH—C(═O)—O—	K005	J081	T072
1044	—(CH2)2—	—NH—C(═O)—O—	K005	J081	T081
1045	—(CH2)2—	—NH—C(═O)—O—	K005	J081	T090
1046	—(CH2)2—	—NH—C(═O)—O—	K005	J081	T099
1047	—(CH2)2—	—NH—C(═O)—O—	K005	J081	T108
1048	—(CH2)2—	—NH—C(═O)—O—	K005	J081	T117
1049	—(CH2)2—	—NH—C(═O)—O—	K005	J081	T126
1050	—(CH2)2—	—NH—C(═O)—O—	K005	J081	T135
1051	—(CH2)2—	—NH—C(═O)—O—	K005	J081	T144
1052	—(CH2)2—	—NH—C(═O)—O—	K005	J081	T153
1053	—(CH2)2—	—NH—C(═O)—O—	K005	J081	T162
1054	—(CH2)2—	—NH—C(═O)—O—	K005	J081	T171
1055	—(CH2)2—	Single bond	K179	J012	T148
1056	—(CH2)2—	Single bond	K180	J045	T148
1057	—(CH2)2—	Single bond	K239	J045	T148
1058	—(CH2)3—	—C(═O)—	K002	J001	T151
1059	—(CH2)3—	—C(═O)—	K002	J012	T151
1060	—(CH2)3—	—C(═O)—	K003	J001	T151
1061	—(CH2)3—	—C(═O)—	K003	J012	T151
1062	—(CH2)3—	—C(═O)—	K004	J001	T151
1063	—(CH2)3—	—C(═O)—	K004	J012	T151
1064	—(CH2)3—	—C(═O)—	K005	J001	T151
1065	—(CH2)3—	—C(═O)—	K005	J012	T151
1066	—(CH2)3—	—C(═O)—	K007	J001	T152
1067	—(CH2)3—	—C(═O)—	K007	J012	T152
1068	—(CH2)3—	—C(═O)—	K008	J001	T152
1069	—(CH2)3—	—C(═O)—	K008	J012	T152
1070	—(CH2)3—	—C(═O)—	K009	J001	T152
1071	—(CH2)3—	—C(═O)—	K009	J012	T152
1072	—(CH2)3—	—C(═O)—	K012	J001	T152
1073	—(CH2)3—	—C(═O)—	K012	J012	T152
1074	—(CH2)3—	—C(═O)—	K107	J001	T168
1075	—(CH2)3—	—C(═O)—	K107	J012	T169
1076	—(CH2)3—	—C(═O)—	K108	J001	T169
1077	—(CH2)3—	—C(═O)—	K108	J012	T169
1078	—(CH2)3—	—C(═O)—	K112	J001	T170
1079	—(CH2)3—	—C(═O)—	K112	J012	T169
1080	—(CH2)3—	—C(═O)—	K129	J001	T171
1081	—(CH2)3—	—C(═O)—	K129	J012	T169
1082	—(CH2)3—	—C(═O)—	K133	J001	T172
1083	—(CH2)3—	—C(═O)—	K133	J012	T169
1084	—(CH2)3—	—C(═O)—	K137	J001	T173
1085	—(CH2)3—	—C(═O)—	K137	J012	T169
1086	—(CH2)3—	—C(═O)—O—	K001	J001	T148
1087	—(CH2)3—	—C(═O)—O—	K002	J001	T151
1088	—(CH2)3—	—C(═O)—O—	K193	J001	T152
1089	—(CH2)3—	—C(═O)—O—	K227	J001	T169
1090	—(CH2)3—	—NH—	K185	J045	T151
1091	—(CH2)3—	—NH—	K185	J045	T169
1092	—(CH2)3—	—NH—C(═O)—	K008	J012	T151
1093	—(CH2)3—	—NH—C(═O)—	K008	J012	T169
1094	—(CH2)3—	—NH—C(═O)—	K013	J001	T151
1095	—(CH2)3—	—NH—C(═O)—	K013	J001	T169
1096	—(CH2)3—	—NH—C(═O)—	K200	J045	T148
1097	—(CH2)3—	—NH—C(═O)—	K200	J045	T152
1098	—(CH2)3—	—NH—C(═O)—NH—	K003	J012	T148
1099	—(CH2)3—	—NH—C(═O)—NH—	K003	J012	T152
1100	—(CH2)3—	—NH—C(═O)—O—	K005	J001	T148
1101	—(CH2)3—	—NH—C(═O)—O—	K005	J001	T152
1102	—CH2—	—C(═O)—	K107	J001	T148
1103	—CH2—	—C(═O)—	K107	J012	T148
1104	—CH2—	—C(═O)—	K107	J018	T148
1105	—CH2—	—C(═O)—	K108	J001	T129
1106	—CH2—	—C(═O)—	K108	J001	T148
1107	—CH2—	—C(═O)—	K108	J001	T151
1108	—CH2—	—C(═O)—	K108	J001	T152
1109	—CH2—	—C(═O)—	K108	J001	T164
1110	—CH2—	—C(═O)—	K108	J001	T170
1111	—CH2—	—C(═O)—	K108	J001	T171
1112	—CH2—	—C(═O)—	K108	J012	T148
1113	—CH2—	—C(═O)—	K108	J022	T148
1114	—CH2—	—C(═O)—	K112	J001	T148
1115	—CH2—	—C(═O)—	K112	J012	T148
1116	—CH2—	—C(═O)—	K129	J001	T148
1117	—CH2—	—C(═O)—	K129	J012	T148
1118	—CH2—	—C(═O)—	K129	J014	T148
1119	—CH2—	—C(═O)—	K133	J001	T148
1120	—CH2—	—C(═O)—	K133	J008	T148
1121	—CH2—	—C(═O)—	K133	J012	T148
1122	—CH2—	—C(═O)—	K137	J001	T129
1123	—CH2—	—C(═O)—	K137	J001	T148
1124	—CH2—	—C(═O)—	K137	J001	T151
1125	—CH2—	—C(═O)—	K137	J001	T152
1126	—CH2—	—C(═O)—	K137	J001	T164
1127	—CH2—	—C(═O)—	K137	J001	T170
1128	—CH2—	—C(═O)—	K137	J001	T172
1129	—CH2—	—C(═O)—	K137	J009	T148
1130	—CH2—	—C(═O)—	K137	J012	T148
1131	—CH2—	—C(═O)—	K237	J001	T148
1132	—CH2—	—C(═O)—NH—	K001	J001	T148
1133	—CH2—	—C(═O)—NH—	K002	J001	T148
1134	—CH2—	—C(═O)—NH—	K002	J012	T148
1135	—CH2—	—C(═O)—NH—	K002	J063	T148
1136	—CH2—	—C(═O)—NH—	K003	J001	T148
1137	—CH2—	—C(═O)—NH—	K003	J012	T148
1138	—CH2—	—C(═O)—NH—	K003	J065	T148
1139	—CH2—	—C(═O)—NH—	K004	J001	T148
1140	—CH2—	—C(═O)—NH—	K004	J012	T148
1141	—CH2—	—C(═O)—NH—	K004	J070	T148
1142	—CH2—	—C(═O)—NH—	K005	J001	T148
1143	—CH2—	—C(═O)—NH—	K005	J012	T148
1144	—CH2—	—C(═O)—NH—	K005	J075	T148
1145	—CH2—	—C(═O)—NH—	K007	J001	T129
1146	—CH2—	—C(═O)—NH—	K007	J001	T148
1147	—CH2—	—C(═O)—NH—	K007	J001	T151
1148	—CH2—	—C(═O)—NH—	K007	J001	T152
1149	—CH2—	—C(═O)—NH—	K007	J001	T164
1150	—CH2—	—C(═O)—NH—	K007	J001	T169
1151	—CH2—	—C(═O)—NH—	K007	J001	T170
1152	—CH2—	—C(═O)—NH—	K007	J012	T148
1153	—CH2—	—C(═O)—NH—	K007	J081	T148
1154	—CH2—	—C(═O)—NH—	K008	J001	T148
1155	—CH2—	—C(═O)—NH—	K008	J012	T148
1156	—CH2—	—C(═O)—NH—	K008	J085	T148
1157	—CH2—	—C(═O)—NH—	K009	J001	T148
1158	—CH2—	—C(═O)—NH—	K009	J012	T148
1159	—CH2—	—C(═O)—NH—	K009	J043	T148
1160	—CH2—	—C(═O)—NH—	K012	J001	T129
1161	—CH2—	—C(═O)—NH—	K012	J001	T148
1162	—CH2—	—C(═O)—NH—	K012	J001	T151
1163	—CH2—	—C(═O)—NH—	K012	J001	T152
1164	—CH2—	—C(═O)—NH—	K012	J001	T164
1165	—CH2—	—C(═O)—NH—	K012	J001	T170
1166	—CH2—	—C(═O)—NH—	K012	J012	T148
1167	—CH2—	—C(═O)—NH—	K012	J045	T148
1168	—CH2—	—C(═O)—NH—	K218	J001	T148
1169	—CH2—	—C(═O)—O—	K001	J001	T148
1170	—CH2—	—C(═O)—O—	K002	J001	T148
1171	—CH2—	—C(═O)—O—	K002	J001	T151
1172	—CH2—	—C(═O)—O—	K193	J001	T152
1173	—CH2—	—C(═O)—O—	K227	J001	T169
1174	Single bond	Single bond	K001	J001	T148
1175	Single bond	Single bond	K001	J002	T148
1176	Single bond	Single bond	K197	J001	T005
1177	Single bond	Single bond	K197	J001	T148
1178	Single bond	Single bond	K197	J012	T148
1179	Single bond	Single bond	K223	J001	T148
1180	Single bond	Single bond	K223	J002	T148
1181	—(CH2)2—	—NH—	K078	J001	T148
1182	—(CH2)2—	—NH—	K078	J045	T148
1183	—(CH2)2—	—NH—	K078	J045	T170
1184	—(CH2)2—	—NH—	K182	J001	T148
1185	—(CH2)2—	—NH—	K372	J045	T148
1186	—(CH2)2—	—NH—	K392	J045	T170
1187	—(CH2)2—	—NH—C(═O)—	K003	J044	T170
1188	—(CH2)2—	—NH—C(═O)—	K004	J007	T148
1189	—(CH2)2—	—NH—C(═O)—	K004	J010	T148
1190	—(CH2)2—	—NH—C(═O)—	K004	J013	T148
1191	—(CH2)2—	—NH—C(═O)—	K004	J014	T148
1192	—(CH2)2—	—NH—C(═O)—	K004	J044	T148
1193	—(CH2)2—	—NH—C(═O)—	K004	J044	T170
1194	—(CH2)2—	—NH—C(═O)—	K006	J007	T148
1195	—(CH2)2—	—NH—C(═O)—	K006	J010	T148
1196	—(CH2)2—	—NH—C(═O)—	K006	J013	T148
1197	—(CH2)2—	—NH—C(═O)—	K007	J007	T148
1198	—(CH2)2—	—NH—C(═O)—	K007	J010	T148
1199	—(CH2)2—	—NH—C(═O)—	K007	J013	T148
1200	—(CH2)2—	—NH—C(═O)—	K007	J014	T148
1201	—(CH2)2—	—NH—C(═O)—	K007	J039	T170
1202	—(CH2)2—	—NH—C(═O)—	K007	J044	T148
1203	—(CH2)2—	—NH—C(═O)—	K007	J044	T169
1204	—(CH2)2—	—NH—C(═O)—	K007	J044	T170
1205	—(CH2)2—	—NH—C(═O)—	K007	J045	T151
1206	—(CH2)2—	—NH—C(═O)—	K007	J045	T170
1207	—(CH2)2—	—NH—C(═O)—	K008	J007	T148
1208	—(CH2)2—	—NH—C(═O)—	K008	J010	T148
1209	—(CH2)2—	—NH—C(═O)—	K008	J013	T148
1210	—(CH2)2—	—NH—C(═O)—	K008	J014	T148
1211	—(CH2)2—	—NH—C(═O)—	K008	J039	T170
1212	—(CH2)2—	—NH—C(═O)—	K008	J044	T148
1213	—(CH2)2—	—NH—C(═O)—	K008	J044	T169
1214	—(CH2)2—	—NH—C(═O)—	K008	J044	T170
1215	—(CH2)2—	—NH—C(═O)—	K008	J045	T151
1216	—(CH2)2—	—NH—C(═O)—	K008	J045	T169
1217	—(CH2)2—	—NH—C(═O)—	K008	J045	T170
1218	—(CH2)2—	—NH—C(═O)—	K009	J007	T148
1219	—(CH2)2—	—NH—C(═O)—	K009	J010	T148
1220	—(CH2)2—	—NH—C(═O)—	K009	J013	T148
1221	—(CH2)2—	—NH—C(═O)—	K009	J014	T148
1222	—(CH2)2—	—NH—C(═O)—	K009	J037	T170
1223	—(CH2)2—	—NH—C(═O)—	K009	J039	T170
1224	—(CH2)2—	—NH—C(═O)—	K009	J043	T170
1225	—(CH2)2—	—NH—C(═O)—	K009	J044	T148
1226	—(CH2)2—	—NH—C(═O)—	K009	J044	T170
1227	—(CH2)2—	—NH—C(═O)—	K009	J045	T152
1228	—(CH2)2—	—NH—C(═O)—	K009	J045	T170
1229	—(CH2)2—	—NH—C(═O)—	K009	J047	T170
1230	—(CH2)2—	—NH—C(═O)—	K009	J145	T148
1231	—(CH2)2—	—NH—C(═O)—	K009	J147	T148
1232	—(CH2)2—	—NH—C(═O)—	K010	J012	T148
1233	—(CH2)2—	—NH—C(═O)—	K010	J012	T164
1234	—(CH2)2—	—NH—C(═O)—	K010	J013	T148
1235	—(CH2)2—	—NH—C(═O)—	K010	J013	T170
1236	—(CH2)2—	—NH—C(═O)—	K010	J045	T148
1237	—(CH2)2—	—NH—C(═O)—	K010	J045	T170
1238	—(CH2)2—	—NH—C(═O)—	K010	J045	T178
1239	—(CH2)2—	—NH—C(═O)—	K010	J045	T179
1240	—(CH2)2—	—NH—C(═O)—	K011	J044	T170
1241	—(CH2)2—	—NH—C(═O)—	K023	J045	T170
1242	—(CH2)2—	—NH—C(═O)—	K033	J045	T170
1243	—(CH2)2—	—NH—C(═O)—	K104	J045	T170
1244	—(CH2)2—	—NH—C(═O)—	K198	J007	T148
1245	—(CH2)2—	—NH—C(═O)—	K198	J010	T148
1246	—(CH2)2—	—NH—C(═O)—	K198	J013	T148
1247	—(CH2)2—	—NH—C(═O)—	K198	J014	T148
1248	—(CH2)2—	—NH—C(═O)—	K198	J039	T170
1249	—(CH2)2—	—NH—C(═O)—	K198	J044	T170
1250	—(CH2)2—	—NH—C(═O)—	K198	J045	T170
1251	—(CH2)2—	—NH—C(═O)—	K199	J007	T148
1252	—(CH2)2—	—NH—C(═O)—	K199	J010	T148
1253	—(CH2)2—	—NH—C(═O)—	K199	J013	T148
1254	—(CH2)2—	—NH—C(═O)—	K199	J014	T148
1255	—(CH2)2—	—NH—C(═O)—	K199	J039	T170
1256	—(CH2)2—	—NH—C(═O)—	K199	J044	T170
1257	—(CH2)2—	—NH—C(═O)—	K199	J045	T170
1258	—(CH2)2—	—NH—C(═O)—	K200	J001	T170
1259	—(CH2)2—	—NH—C(═O)—	K200	J002	T170
1260	—(CH2)2—	—NH—C(═O)—	K200	J007	T148
1261	—(CH2)2—	—NH—C(═O)—	K200	J007	T170
1262	—(CH2)2—	—NH—C(═O)—	K200	J008	T170
1263	—(CH2)2—	—NH—C(═O)—	K200	J009	T164
1264	—(CH2)2—	—NH—C(═O)—	K200	J009	T170
1265	—(CH2)2—	—NH—C(═O)—	K200	J010	T148
1266	—(CH2)2—	—NH—C(═O)—	K200	J010	T170
1267	—(CH2)2—	—NH—C(═O)—	K200	J011	T148
1268	—(CH2)2—	—NH—C(═O)—	K200	J011	T164
1269	—(CH2)2—	—NH—C(═O)—	K200	J011	T170
1270	—(CH2)2—	—NH—C(═O)—	K200	J012	T164
1271	—(CH2)2—	—NH—C(═O)—	K200	J012	T170
1272	—(CH2)2—	—NH—C(═O)—	K200	J013	T148
1273	—(CH2)2—	—NH—C(═O)—	K200	J013	T170
1274	—(CH2)2—	—NH—C(═O)—	K200	J014	T148
1275	—(CH2)2—	—NH—C(═O)—	K200	J037	T148
1276	—(CH2)2—	—NH—C(═O)—	K200	J037	T169
1277	—(CH2)2—	—NH—C(═O)—	K200	J037	T170
1278	—(CH2)2—	—NH—C(═O)—	K200	J038	T170
1279	—(CH2)2—	—NH—C(═O)—	K200	J039	T148
1280	—(CH2)2—	—NH—C(═O)—	K200	J039	T164
1281	—(CH2)2—	—NH—C(═O)—	K200	J039	T170
1282	—(CH2)2—	—NH—C(═O)—	K200	J043	T148
1283	—(CH2)2—	—NH—C(═O)—	K200	J043	T169
1284	—(CH2)2—	—NH—C(═O)—	K200	J043	T170
1285	—(CH2)2—	—NH—C(═O)—	K200	J044	T148
1286	—(CH2)2—	—NH—C(═O)—	K200	J044	T170
1287	—(CH2)2—	—NH—C(═O)—	K200	J045	T164
1288	—(CH2)2—	—NH—C(═O)—	K200	J045	T170
1289	—(CH2)2—	—NH—C(═O)—	K200	J045	T171
1290	—(CH2)2—	—NH—C(═O)—	K200	J045	T177
1291	—(CH2)2—	—NH—C(═O)—	K200	J045	T178
1292	—(CH2)2—	—NH—C(═O)—	K200	J045	T179
1293	—(CH2)2—	—NH—C(═O)—	K200	J045	T180
1294	—(CH2)2—	—NH—C(═O)—	K200	J047	T148
1295	—(CH2)2—	—NH—C(═O)—	K200	J047	T169
1296	—(CH2)2—	—NH—C(═O)—	K200	J047	T170
1297	—(CH2)2—	—NH—C(═O)—	K200	J079	T148
1298	—(CH2)2—	—NH—C(═O)—	K200	J079	T169
1299	—(CH2)2—	—NH—C(═O)—	K200	J079	T170
1300	—(CH2)2—	—NH—C(═O)—	K200	J080	T148
1301	—(CH2)2—	—NH—C(═O)—	K200	J080	T169
1302	—(CH2)2—	—NH—C(═O)—	K200	J080	T170
1303	—(CH2)2—	—NH—C(═O)—	K200	J081	T148
1304	—(CH2)2—	—NH—C(═O)—	K200	J081	T164
1305	—(CH2)2—	—NH—C(═O)—	K200	J081	T170
1306	—(CH2)2—	—NH—C(═O)—	K200	J082	T148
1307	—(CH2)2—	—NH—C(═O)—	K200	J082	T169
1308	—(CH2)2—	—NH—C(═O)—	K200	J082	T170
1309	—(CH2)2—	—NH—C(═O)—	K200	J090	T148
1310	—(CH2)2—	—NH—C(═O)—	K200	J090	T169
1311	—(CH2)2—	—NH—C(═O)—	K200	J090	T170
1312	—(CH2)2—	—NH—C(═O)—	K200	J092	T148
1313	—(CH2)2—	—NH—C(═O)—	K200	J092	T164
1314	—(CH2)2—	—NH—C(═O)—	K200	J092	T170
1315	—(CH2)2—	—NH—C(═O)—	K200	J093	T148
1316	—(CH2)2—	—NH—C(═O)—	K200	J103	T148
1317	—(CH2)2—	—NH—C(═O)—	K200	J103	T164
1318	—(CH2)2—	—NH—C(═O)—	K200	J103	T170
1319	—(CH2)2—	—NH—C(═O)—	K200	J104	T148
1320	—(CH2)2—	—NH—C(═O)—	K200	J104	T164
1321	—(CH2)2—	—NH—C(═O)—	K200	J104	T170
1322	—(CH2)2—	—NH—C(═O)—	K200	J105	T148
1323	—(CH2)2—	—NH—C(═O)—	K200	J105	T164
1324	—(CH2)2—	—NH—C(═O)—	K200	J105	T169
1325	—(CH2)2—	—NH—C(═O)—	K200	J106	T148
1326	—(CH2)2—	—NH—C(═O)—	K200	J106	T164
1327	—(CH2)2—	—NH—C(═O)—	K200	J106	T170
1328	—(CH2)2—	—NH—C(═O)—	K200	J107	T148
1329	—(CH2)2—	—NH—C(═O)—	K200	J107	T164
1330	—(CH2)2—	—NH—C(═O)—	K200	J107	T170
1331	—(CH2)2—	—NH—C(═O)—	K200	J109	T170
1332	—(CH2)2—	—NH—C(═O)—	K200	J118	T170
1333	—(CH2)2—	—NH—C(═O)—	K200	J138	T170
1334	—(CH2)2—	—NH—C(═O)—	K200	J139	T170
1335	—(CH2)2—	—NH—C(═O)—	K200	J144	T148
1336	—(CH2)2—	—NH—C(═O)—	K200	J144	T169
1337	—(CH2)2—	—NH—C(═O)—	K200	J144	T170
1338	—(CH2)2—	—NH—C(═O)—	K200	J145	T170
1339	—(CH2)2—	—NH—C(═O)—	K200	J146	T148
1340	—(CH2)2—	—NH—C(═O)—	K200	J146	T164
1341	—(CH2)2—	—NH—C(═O)—	K200	J105	T170
1342	—(CH2)2—	—NH—C(═O)—	K200	J147	T148
1343	—(CH2)2—	—NH—C(═O)—	K200	J147	T170
1344	—(CH2)2—	—NH—C(═O)—	K200	J148	T148
1345	—(CH2)2—	—NH—C(═O)—	K200	J149	T148
1346	—(CH2)2—	—NH—C(═O)—	K200	J149	T170
1347	—(CH2)2—	—NH—C(═O)—	K200	J150	T148
1348	—(CH2)2—	—NH—C(═O)—	K200	J150	T170
1349	—(CH2)2—	—NH—C(═O)—	K200	J151	T148
1350	—(CH2)2—	—NH—C(═O)—	K200	J151	T170
1351	—(CH2)2—	—NH—C(═O)—	K200	J152	T148
1352	—(CH2)2—	—NH—C(═O)—	K200	J153	T148
1353	—(CH2)2—	—NH—C(═O)—	K200	J154	T148
1354	—(CH2)2—	—NH—C(═O)—	K200	J155	T148
1355	—(CH2)2—	—NH—C(═O)—	K200	J156	T148
1356	—(CH2)2—	—NH—C(═O)—	K200	J157	T148
1357	—(CH2)2—	—NH—C(═O)—	K200	J158	T148
1358	—(CH2)2—	—NH—C(═O)—	K200	J158	T170
1359	—(CH2)2—	—NH—C(═O)—	K200	J159	T148
1360	—(CH2)2—	—NH—C(═O)—	K200	J159	T170
1361	—(CH2)2—	—NH—C(═O)—	K201	J007	T148
1362	—(CH2)2—	—NH—C(═O)—	K201	J008	T148
1363	—(CH2)2—	—NH—C(═O)—	K201	J010	T148
1364	—(CH2)2—	—NH—C(═O)—	K201	J012	T148
1365	—(CH2)2—	—NH—C(═O)—	K201	J013	T148
1366	—(CH2)2—	—NH—C(═O)—	K201	J014	T148
1367	—(CH2)2—	—NH—C(═O)—	K201	J037	T170
1368	—(CH2)2—	—NH—C(═O)—	K201	J039	T170
1369	—(CH2)2—	—NH—C(═O)—	K201	J043	T170
1370	—(CH2)2—	—NH—C(═O)—	K201	J044	T148
1371	—(CH2)2—	—NH—C(═O)—	K201	J044	T170
1372	—(CH2)2—	—NH—C(═O)—	K201	J045	T148
1373	—(CH2)2—	—NH—C(═O)—	K201	J045	T152
1374	—(CH2)2—	—NH—C(═O)—	K201	J045	T170
1375	—(CH2)2—	—NH—C(═O)—	K201	J047	T170
1376	—(CH2)2—	—NH—C(═O)—	K201	J145	T148
1377	—(CH2)2—	—NH—C(═O)—	K201	J147	T148
1378	—(CH2)2—	—NH—C(═O)—	K202	J007	T148
1379	—(CH2)2—	—NH—C(═O)—	K202	J008	T148
1380	—(CH2)2—	—NH—C(═O)—	K202	J010	T148
1381	—(CH2)2—	—NH—C(═O)—	K202	J012	T148
1382	—(CH2)2—	—NH—C(═O)—	K202	J013	T148
1383	—(CH2)2—	—NH—C(═O)—	K202	J014	T148
1384	—(CH2)2—	—NH—C(═O)—	K202	J039	T170
1385	—(CH2)2—	—NH—C(═O)—	K202	J044	T148
1386	—(CH2)2—	—NH—C(═O)—	K202	J044	T164
1387	—(CH2)2—	—NH—C(═O)—	K202	J044	T170
1388	—(CH2)2—	—NH—C(═O)—	K202	J045	T148
1389	—(CH2)2—	—NH—C(═O)—	K202	J045	T164
1390	—(CH2)2—	—NH—C(═O)—	K203	J007	T148
1391	—(CH2)2—	—NH—C(═O)—	K203	J010	T148
1392	—(CH2)2—	—NH—C(═O)—	K203	J013	T148
1393	—(CH2)2—	—NH—C(═O)—	K203	J014	T148
1394	—(CH2)2—	—NH—C(═O)—	K203	J039	T170
1395	—(CH2)2—	—NH—C(═O)—	K203	J044	T148
1396	—(CH2)2—	—NH—C(═O)—	K203	J044	T164
1397	—(CH2)2—	—NH—C(═O)—	K203	J044	T170
1398	—(CH2)2—	—NH—C(═O)—	K203	J045	T164
1399	—(CH2)2—	—NH—C(═O)—	K203	J045	T170
1400	—(CH2)2—	—NH—C(═O)—	K204	J007	T148
1401	—(CH2)2—	—NH—C(═O)—	K204	J008	T148
1402	—(CH2)2—	—NH—C(═O)—	K204	J009	T170
1403	—(CH2)2—	—NH—C(═O)—	K204	J010	T148
1404	—(CH2)2—	—NH—C(═O)—	K204	J011	T170
1405	—(CH2)2—	—NH—C(═O)—	K204	J012	T148
1406	—(CH2)2—	—NH—C(═O)—	K204	J013	T148
1407	—(CH2)2—	—NH—C(═O)—	K204	J037	T170
1408	—(CH2)2—	—NH—C(═O)—	K204	J039	T170
1409	—(CH2)2—	—NH—C(═O)—	K204	J043	T170
1410	—(CH2)2—	—NH—C(═O)—	K204	J044	T148
1411	—(CH2)2—	—NH—C(═O)—	K204	J044	T169
1412	—(CH2)2—	—NH—C(═O)—	K204	J044	T170
1413	—(CH2)2—	—NH—C(═O)—	K204	J045	T148
1414	—(CH2)2—	—NH—C(═O)—	K204	J045	T169
1415	—(CH2)2—	—NH—C(═O)—	K204	J045	T170
1416	—(CH2)2—	—NH—C(═O)—	K204	J047	T170
1417	—(CH2)2—	—NH—C(═O)—	K204	J079	T170
1418	—(CH2)2—	—NH—C(═O)—	K204	J145	T148
1419	—(CH2)2—	—NH—C(═O)—	K204	J147	T148
1420	—(CH2)2—	—NH—C(═O)—	K205	J007	T148
1421	—(CH2)2—	—NH—C(═O)—	K205	J008	T148
1422	—(CH2)2—	—NH—C(═O)—	K205	J010	T148
1423	—(CH2)2—	—NH—C(═O)—	K205	J012	T148
1424	—(CH2)2—	—NH—C(═O)—	K205	J013	T148
1425	—(CH2)2—	—NH—C(═O)—	K205	J014	T148
1426	—(CH2)2—	—NH—C(═O)—	K205	J044	T170
1427	—(CH2)2—	—NH—C(═O)—	K205	J045	T170
1428	—(CH2)2—	—NH—C(═O)—	K206	J039	T170
1429	—(CH2)2—	—NH—C(═O)—	K206	J044	T170
1430	—(CH2)2—	—NH—C(═O)—	K206	J045	T170
1431	—(CH2)2—	—NH—C(═O)—	K207	J044	T170
1432	—(CH2)2—	—NH—C(═O)—	K208	J007	T148
1433	—(CH2)2—	—NH—C(═O)—	K208	J009	T170
1434	—(CH2)2—	—NH—C(═O)—	K208	J010	T148
1435	—(CH2)2—	—NH—C(═O)—	K208	J011	T170
1436	—(CH2)2—	—NH—C(═O)—	K208	J013	T148
1437	—(CH2)2—	—NH—C(═O)—	K208	J014	T148
1438	—(CH2)2—	—NH—C(═O)—	K208	J037	T170
1439	—(CH2)2—	—NH—C(═O)—	K208	J039	T170
1440	—(CH2)2—	—NH—C(═O)—	K208	J043	T170
1441	—(CH2)2—	—NH—C(═O)—	K208	J044	T148
1442	—(CH2)2—	—NH—C(═O)—	K208	J044	T169
1443	—(CH2)2—	—NH—C(═O)—	K208	J044	T170
1444	—(CH2)2—	—NH—C(═O)—	K208	J045	T169
1445	—(CH2)2—	—NH—C(═O)—	K208	J045	T170
1446	—(CH2)2—	—NH—C(═O)—	K208	J047	T170
1447	—(CH2)2—	—NH—C(═O)—	K208	J079	T170
1448	—(CH2)2—	—NH—C(═O)—	K208	J145	T148
1449	—(CH2)2—	—NH—C(═O)—	K208	J147	T148
1450	—(CH2)2—	—NH—C(═O)—	K209	J007	T148
1451	—(CH2)2—	—NH—C(═O)—	K209	J010	T148
1452	—(CH2)2—	—NH—C(═O)—	K209	J013	T148
1453	—(CH2)2—	—NH—C(═O)—	K209	J014	T148
1454	—(CH2)2—	—NH—C(═O)—	K209	J044	T170
1455	—(CH2)2—	—NH—C(═O)—	K210	J007	T148
1456	—(CH2)2—	—NH—C(═O)—	K210	J010	T148
1457	—(CH2)2—	—NH—C(═O)—	K210	J013	T148
1458	—(CH2)2—	—NH—C(═O)—	K210	J014	T148
1459	—(CH2)2—	—NH—C(═O)—	K210	J044	T170
1460	—(CH2)2—	—NH—C(═O)—	K213	J007	T148
1461	—(CH2)2—	—NH—C(═O)—	K213	J008	T148
1462	—(CH2)2—	—NH—C(═O)—	K213	J010	T148
1463	—(CH2)2—	—NH—C(═O)—	K213	J012	T148
1464	—(CH2)2—	—NH—C(═O)—	K213	J013	T148
1465	—(CH2)2—	—NH—C(═O)—	K213	J014	T148
1466	—(CH2)2—	—NH—C(═O)—	K213	J044	T170
1467	—(CH2)2—	—NH—C(═O)—	K214	J007	T148
1468	—(CH2)2—	—NH—C(═O)—	K214	J008	T148
1469	—(CH2)2—	—NH—C(═O)—	K214	J010	T148
1470	—(CH2)2—	—NH—C(═O)—	K214	J012	T148
1471	—(CH2)2—	—NH—C(═O)—	K214	J013	T148
1472	—(CH2)2—	—NH—C(═O)—	K214	J014	T148
1473	—(CH2)2—	—NH—C(═O)—	K214	J044	T170
1474	—(CH2)2—	—NH—C(═O)—	K215	J007	T148
1475	—(CH2)2—	—NH—C(═O)—	K215	J010	T148
1476	—(CH2)2—	—NH—C(═O)—	K215	J013	T148
1477	—(CH2)2—	—NH—C(═O)—	K215	J014	T148
1478	—(CH2)2—	—NH—C(═O)—	K215	J044	T170
1479	—(CH2)2—	—NH—C(═O)—	K216	J007	T148
1480	—(CH2)2—	—NH—C(═O)—	K216	J008	T148
1481	—(CH2)2—	—NH—C(═O)—	K216	J010	T148
1482	—(CH2)2—	—NH—C(═O)—	K216	J012	T148
1483	—(CH2)2—	—NH—C(═O)—	K216	J013	T148
1484	—(CH2)2—	—NH—C(═O)—	K216	J014	T148
1485	—(CH2)2—	—NH—C(═O)—	K216	J044	T170
1486	—(CH2)2—	—NH—C(═O)—	K216	J045	T170
1487	—(CH2)2—	—NH—C(═O)—	K217	J007	T148
1488	—(CH2)2—	—NH—C(═O)—	K217	J008	T148
1489	—(CH2)2—	—NH—C(═O)—	K217	J010	T148
1490	—(CH2)2—	—NH—C(═O)—	K217	J012	T148
1491	—(CH2)2—	—NH—C(═O)—	K217	J013	T148
1492	—(CH2)2—	—NH—C(═O)—	K217	J014	T148
1493	—(CH2)2—	—NH—C(═O)—	K217	J044	T170
1494	—(CH2)2—	—NH—C(═O)—	K217	J045	T170
1495	—(CH2)2—	—NH—C(═O)—	K218	J007	T148
1496	—(CH2)2—	—NH—C(═O)—	K218	J008	T148
1497	—(CH2)2—	—NH—C(═O)—	K218	J010	T148
1498	—(CH2)2—	—NH—C(═O)—	K218	J012	T148
1499	—(CH2)2—	—NH—C(═O)—	K218	J012	T164
1500	—(CH2)2—	—NH—C(═O)—	K218	J013	T148
1501	—(CH2)2—	—NH—C(═O)—	K218	J013	T170
1502	—(CH2)2—	—NH—C(═O)—	K218	J014	T148
1503	—(CH2)2—	—NH—C(═O)—	K218	J044	T170
1504	—(CH2)2—	—NH—C(═O)—	K218	J045	T170
1505	—(CH2)2—	—NH—C(═O)—	K218	J045	T178
1506	—(CH2)2—	—NH—C(═O)—	K218	J045	T179
1507	—(CH2)2—	—NH—C(═O)—	K222	J007	T148
1508	—(CH2)2—	—NH—C(═O)—	K222	J010	T148
1509	—(CH2)2—	—NH—C(═O)—	K222	J013	T148
1510	—(CH2)2—	—NH—C(═O)—	K222	J014	T148
1511	—(CH2)2—	—NH—C(═O)—	K240	J045	T148
1512	—(CH2)2—	—NH—C(═O)—	K242	J045	T169
1513	—(CH2)2—	—NH—C(═O)—	K242	J045	T170
1514	—(CH2)2—	—NH—C(═O)—	K243	J045	T170
1515	—(CH2)2—	—NH—C(═O)—	K244	J045	T169
1516	—(CH2)2—	—NH—C(═O)—	K244	J045	T170
1517	—(CH2)2—	—NH—C(═O)—	K245	J045	T170
1518	—(CH2)2—	—NH—C(═O)—	K246	J045	T170
1519	—(CH2)2—	—NH—C(═O)—	K247	J012	T148
1520	—(CH2)2—	—NH—C(═O)—	K247	J045	T148
1521	—(CH2)2—	—NH—C(═O)—	K247	J045	T170
1522	—(CH2)2—	—NH—C(═O)—	K248	J045	T148
1523	—(CH2)2—	—NH—C(═O)—	K248	J045	T170
1524	—(CH2)2—	—NH—C(═O)—	K249	J007	T148
1525	—(CH2)2—	—NH—C(═O)—	K249	J008	T148
1526	—(CH2)2—	—NH—C(═O)—	K249	J010	T148
1527	—(CH2)2—	—NH—C(═O)—	K249	J013	T148
1528	—(CH2)2—	—NH—C(═O)—	K249	J014	T148
1529	—(CH2)2—	—NH—C(═O)—	K249	J045	T170
1530	—(CH2)2—	—NH—C(═O)—	K250	J045	T148
1531	—(CH2)2—	—NH—C(═O)—	K250	J045	T170
1532	—(CH2)2—	—NH—C(═O)—	K251	J045	T170
1533	—(CH2)2—	—NH—C(═O)—	K252	J045	T148
1534	—(CH2)2—	—NH—C(═O)—	K252	J045	T170
1535	—(CH2)2—	—NH—C(═O)—	K253	J045	T148
1536	—(CH2)2—	—NH—C(═O)—	K253	J045	T170
1537	—(CH2)2—	—NH—C(═O)—	K254	J007	T148
1538	—(CH2)2—	—NH—C(═O)—	K254	J008	T148
1539	—(CH2)2—	—NH—C(═O)—	K254	J010	T148
1540	—(CH2)2—	—NH—C(═O)—	K254	J012	T148
1541	—(CH2)2—	—NH—C(═O)—	K254	J013	T148
1542	—(CH2)2—	—NH—C(═O)—	K254	J014	T148
1543	—(CH2)2—	—NH—C(═O)—	K254	J044	T170
1544	—(CH2)2—	—NH—C(═O)—	K254	J045	T169
1545	—(CH2)2—	—NH—C(═O)—	K254	J045	T170
1546	—(CH2)2—	—NH—C(═O)—	K255	J012	T148
1547	—(CH2)2—	—NH—C(═O)—	K255	J045	T169
1548	—(CH2)2—	—NH—C(═O)—	K255	J045	T170
1549	—(CH2)2—	—NH—C(═O)—	K256	J012	T148
1550	—(CH2)2—	—NH—C(═O)—	K256	J039	T170
1551	—(CH2)2—	—NH—C(═O)—	K256	J044	T170
1552	—(CH2)2—	—NH—C(═O)—	K256	J045	T169
1553	—(CH2)2—	—NH—C(═O)—	K256	J045	T170
1554	—(CH2)2—	—NH—C(═O)—	K257	J012	T148
1555	—(CH2)2—	—NH—C(═O)—	K257	J039	T170
1556	—(CH2)2—	—NH—C(═O)—	K257	J044	T170
1557	—(CH2)2—	—NH—C(═O)—	K257	J045	T169
1558	—(CH2)2—	—NH—C(═O)—	K257	J045	T170
1559	—(CH2)2—	—NH—C(═O)—	K258	J012	T148
1560	—(CH2)2—	—NH—C(═O)—	K258	J045	T169
1561	—(CH2)2—	—NH—C(═O)—	K258	J045	T170
1562	—(CH2)2—	—NH—C(═O)—	K259	J012	T148
1563	—(CH2)2—	—NH—C(═O)—	K259	J039	T170
1564	—(CH2)2—	—NH—C(═O)—	K259	J044	T170
1565	—(CH2)2—	—NH—C(═O)—	K259	J045	T169
1566	—(CH2)2—	—NH—C(═O)—	K259	J045	T170
1567	—(CH2)2—	—NH—C(═O)—	K260	J012	T148
1568	—(CH2)2—	—NH—C(═O)—	K260	J045	T169
1569	—(CH2)2—	—NH—C(═O)—	K260	J045	T170
1570	—(CH2)2—	—NH—C(═O)—	K261	J012	T148
1571	—(CH2)2—	—NH—C(═O)—	K261	J045	T169
1572	—(CH2)2—	—NH—C(═O)—	K261	J045	T170
1573	—(CH2)2—	—NH—C(═O)—	K262	J007	T148
1574	—(CH2)2—	—NH—C(═O)—	K262	J008	T148
1575	—(CH2)2—	—NH—C(═O)—	K262	J010	T148
1576	—(CH2)2—	—NH—C(═O)—	K262	J012	T148
1577	—(CH2)2—	—NH—C(═O)—	K262	J013	T148
1578	—(CH2)2—	—NH—C(═O)—	K262	J014	T148
1579	—(CH2)2—	—NH—C(═O)—	K262	J044	T148
1580	—(CH2)2—	—NH—C(═O)—	K262	J044	T170
1581	—(CH2)2—	—NH—C(═O)—	K262	J044	T178
1582	—(CH2)2—	—NH—C(═O)—	K262	J045	T148
1583	—(CH2)2—	—NH—C(═O)—	K262	J045	T169
1584	—(CH2)2—	—NH—C(═O)—	K262	J045	T170
1585	—(CH2)2—	—NH—C(═O)—	K262	J045	T178
1586	—(CH2)2—	—NH—C(═O)—	K263	J007	T148
1587	—(CH2)2—	—NH—C(═O)—	K263	J008	T148
1588	—(CH2)2—	—NH—C(═O)—	K263	J010	T148
1589	—(CH2)2—	—NH—C(═O)—	K263	J012	T148
1590	—(CH2)2—	—NH—C(═O)—	K263	J012	T164
1591	—(CH2)2—	—NH—C(═O)—	K263	J013	T148
1592	—(CH2)2—	—NH—C(═O)—	K263	J013	T170
1593	—(CH2)2—	—NH—C(═O)—	K263	J014	T148
1594	—(CH2)2—	—NH—C(═O)—	K263	J039	T170
1595	—(CH2)2—	—NH—C(═O)—	K263	J044	T148
1596	—(CH2)2—	—NH—C(═O)—	K263	J044	T170
1597	—(CH2)2—	—NH—C(═O)—	K263	J044	T179
1598	—(CH2)2—	—NH—C(═O)—	K263	J045	T148
1599	—(CH2)2—	—NH—C(═O)—	K263	J045	T169
1600	—(CH2)2—	—NH—C(═O)—	K263	J045	T170
1601	—(CH2)2—	—NH—C(═O)—	K263	J045	T178
1602	—(CH2)2—	—NH—C(═O)—	K263	J045	T179
1603	—(CH2)2—	—NH—C(═O)—	K264	J012	T148
1604	—(CH2)2—	—NH—C(═O)—	K264	J045	T169
1605	—(CH2)2—	—NH—C(═O)—	K264	J045	T170
1606	—(CH2)2—	—NH—C(═O)—	K265	J012	T148
1607	—(CH2)2—	—NH—C(═O)—	K265	J044	T148
1608	—(CH2)2—	—NH—C(═O)—	K265	J044	T180
1609	—(CH2)2—	—NH—C(═O)—	K265	J045	T148
1610	—(CH2)2—	—NH—C(═O)—	K265	J045	T169
1611	—(CH2)2—	—NH—C(═O)—	K265	J045	T170
1612	—(CH2)2—	—NH—C(═O)—	K265	J045	T180
1613	—(CH2)2—	—NH—C(═O)—	K266	J012	T148
1614	—(CH2)2—	—NH—C(═O)—	K266	J045	T169
1615	—(CH2)2—	—NH—C(═O)—	K266	J045	T170
1616	—(CH2)2—	—NH—C(═O)—	K267	J012	T148
1617	—(CH2)2—	—NH—C(═O)—	K267	J045	T169
1618	—(CH2)2—	—NH—C(═O)—	K267	J045	T170
1619	—(CH2)2—	—NH—C(═O)—	K268	J012	T148
1620	—(CH2)2—	—NH—C(═O)—	K268	J045	T170
1621	—(CH2)2—	—NH—C(═O)—	K269	J012	T148
1622	—(CH2)2—	—NH—C(═O)—	K269	J045	T170
1623	—(CH2)2—	—NH—C(═O)—	K210	J012	T148
1624	—(CH2)2—	—NH—C(═O)—	K270	J045	T170
1625	—(CH2)2—	—NH—C(═O)—	K271	J012	T148
1626	—(CH2)2—	—NH—C(═O)—	K271	J045	T169
1627	—(CH2)2—	—NH—C(═O)—	K271	J045	T170
1628	—(CH2)2—	—NH—C(═O)—	K272	J012	T148
1629	—(CH2)2—	—NH—C(═O)—	K272	J045	T169
1630	—(CH2)2—	—NH—C(═O)—	K272	J045	T170
1631	—(CH2)2—	—NH—C(═O)—	K273	J012	T148
1632	—(CH2)2—	—NH—C(═O)—	K273	J045	T170
1633	—(CH2)2—	—NH—C(═O)—	K274	J012	T148
1634	—(CH2)2—	—NH—C(═O)—	K274	J045	T170
1635	—(CH2)2—	—NH—C(═O)—	K275	J007	T148
1636	—(CH2)2—	—NH—C(═O)—	K275	J008	T148
1637	—(CH2)2—	—NH—C(═O)—	K275	J010	T148
1638	—(CH2)2—	—NH—C(═O)—	K275	J012	T148
1639	—(CH2)2—	—NH—C(═O)—	K275	J013	T148
1640	—(CH2)2—	—NH—C(═O)—	K275	J014	T148
1641	—(CH2)2—	—NH—C(═O)—	K275	J044	T170
1642	—(CH2)2—	—NH—C(═O)—	K275	J045	T169
1643	—(CH2)2—	—NH—C(═O)—	K275	J045	T170
1644	—(CH2)2—	—NH—C(═O)—	K276	J007	T148
1645	—(CH2)2—	—NH—C(═O)—	K276	J008	T148
1646	—(CH2)2—	—NH—C(═O)—	K276	J010	T148
1647	—(CH2)2—	—NH—C(═O)—	K276	J012	T148
1648	—(CH2)2—	—NH—C(═O)—	K276	J012	T164
1649	—(CH2)2—	—NH—C(═O)—	K276	J013	T148
1650	—(CH2)2—	—NH—C(═O)—	K276	J013	T170
1651	—(CH2)2—	—NH—C(═O)—	K276	J014	T148
1652	—(CH2)2—	—NH—C(═O)—	K276	J044	T170
1653	—(CH2)2—	—NH—C(═O)—	K276	J045	T169
1654	—(CH2)2—	—NH—C(═O)—	K276	J045	T170
1655	—(CH2)2—	—NH—C(═O)—	K276	J045	T178
1656	—(CH2)2—	—NH—C(═O)—	K276	J045	T179
1657	—(CH2)2—	—NH—C(═O)—	K277	J045	T170
1658	—(CH2)2—	—NH—C(═O)—	K278	J045	T170
1659	—(CH2)2—	—NH—C(═O)—	K279	J045	T170
1660	—(CH2)2—	—NH—C(═O)—	K280	J012	T148
1661	—(CH2)2—	—NH—C(═O)—	K280	J045	T170
1662	—(CH2)2—	—NH—C(═O)—	K281	J045	T170
1663	—(CH2)2—	—NH—C(═O)—	K282	J045	T170
1664	—(CH2)2—	—NH—C(═O)—	K283	J045	T170
1665	—(CH2)2—	—NH—C(═O)—	K284	J045	T170
1666	—(CH2)2—	—NH—C(═O)—	K285	J045	T170
1667	—(CH2)2—	—NH—C(═O)—	K286	J045	T170
1668	—(CH2)2—	—NH—C(═O)—	K287	J045	T170
1669	—(CH2)2—	—NH—C(═O)—	K288	J045	T170
1670	—(CH2)2—	—NH—C(═O)—	K289	J007	T148
1671	—(CH2)2—	—NH—C(═O)—	K289	J008	T148
1672	—(CH2)2—	—NH—C(═O)—	K289	J010	T148
1673	—(CH2)2—	—NH—C(═O)—	K289	J012	T148
1674	—(CH2)2—	—NH—C(═O)—	K289	J013	T148
1675	—(CH2)2—	—NH—C(═O)—	K289	J014	T148
1676	—(CH2)2—	—NH—C(═O)—	K289	J044	T169
1677	—(CH2)2—	—NH—C(═O)—	K289	J044	T170
1678	—(CH2)2—	—NH—C(═O)—	K289	J045	T169
1679	—(CH2)2—	—NH—C(═O)—	K289	J045	T170
1680	—(CH2)2—	—NH—C(═O)—	K290	J045	T170
1681	—(CH2)2—	—NH—C(═O)—	K291	J045	T170
1682	—(CH2)2—	—NH—C(═O)—	K292	J045	T148
1683	—(CH2)2—	—NH—C(═O)—	K292	J045	T170
1684	—(CH2)2—	—NH—C(═O)—	K293	J007	T148
1685	—(CH2)2—	—NH—C(═O)—	K293	J008	T148
1686	—(CH2)2—	—NH—C(═O)—	K293	J010	T148
1687	—(CH2)2—	—NH—C(═O)—	K293	J012	T148
1688	—(CH2)2—	—NH—C(═O)—	K293	J013	T148
1689	—(CH2)2—	—NH—C(═O)—	K293	J014	T148
1690	—(CH2)2—	—NH—C(═O)—	K293	J044	T170
1691	—(CH2)2—	—NH—C(═O)—	K293	J045	T148
1692	—(CH2)2—	—NH—C(═O)—	K293	J045	T169
1693	—(CH2)2—	—NH—C(═O)—	K293	J045	T170
1694	—(CH2)2—	—NH—C(═O)—	K294	J045	T170
1695	—(CH2)2—	—NH—C(═O)—	K295	J045	T170
1696	—(CH2)2—	—NH—C(═O)—	K295/K296	J045	T148
1697	—(CH2)2—	—NH—C(═O)—	K296	J045	T170
1698	—(CH2)2—	—NH—C(═O)—	K297	J045	T170
1699	—(CH2)2—	—NH—C(═O)—	K298	J045	T148
1700	—(CH2)2—	—NH—C(═O)—	K298	J045	T170
1701	—(CH2)2—	—NH—C(═O)—	K299	J045	T170
1702	—(CH2)2—	—NH—C(═O)—	K300	J045	T170
1703	—(CH2)2—	—NH—C(═O)—	K301	J044	T170
1704	—(CH2)2—	—NH—C(═O)—	K301	J045	T169
1705	—(CH2)2—	—NH—C(═O)—	K301	J045	T170
1706	—(CH2)2—	—NH—C(═O)—	K302	J012	T148
1707	—(CH2)2—	—NH—C(═O)—	K302	J044	T170
1708	—(CH2)2—	—NH—C(═O)—	K302	J045	T170
1709	—(CH2)2—	—NH—C(═O)—	K303	J007	T148
1710	—(CH2)2—	—NH—C(═O)—	K303	J008	T148
1711	—(CH2)2—	—NH—C(═O)—	K303	J010	T148
1712	—(CH2)2—	—NH—C(═O)—	K303	J013	T148
1713	—(CH2)2—	—NH—C(═O)—	K303	J014	T148
1714	—(CH2)2—	—NH—C(═O)—	K303	J044	T170
1715	—(CH2)2—	—NH—C(═O)—	K303	J045	T148
1716	—(CH2)2—	—NH—C(═O)—	K303	J045	T169
1717	—(CH2)2—	—NH—C(═O)—	K303	J045	T170
1718	—(CH2)2—	—NH—C(═O)—	K304	J012	T148
1719	—(CH2)2—	—NH—C(═O)—	K304	J045	T148
1720	—(CH2)2—	—NH—C(═O)—	K304	J045	T170
1721	—(CH2)2—	—NH—C(═O)—	K305	J045	T148
1722	—(CH2)2—	—NH—C(═O)—	K305	J045	T170
1723	—(CH2)2—	—NH—C(═O)—	K306	J044	T170
1724	—(CH2)2—	—NH—C(═O)—	K306	J045	T170
1725	—(CH2)2—	—NH—C(═O)—	K307	J045	T170
1726	—(CH2)2—	—NH—C(═O)—	K308	J007	T148
1727	—(CH2)2—	—NH—C(═O)—	K308	J008	T148
1728	—(CH2)2—	—NH—C(═O)—	K308	J010	T148
1729	—(CH2)2—	—NH—C(═O)—	K308	J012	T148
1730	—(CH2)2—	—NH—C(═O)—	K308	J013	T148
1731	—(CH2)2—	—NH—C(═O)—	K308	J014	T148
1732	—(CH2)2—	—NH—C(═O)—	K308	J045	T170
1733	—(CH2)2—	—NH—C(═O)—	K309	J045	T170
1734	—(CH2)2—	—NH—C(═O)—	K310	J045	T170
1735	—(CH2)2—	—NH—C(═O)—	K311	J045	T170
1736	—(CH2)2—	—NH—C(═O)—	K312	J012	T148
1737	—(CH2)2—	—NH—C(═O)—	K312	J045	T170
1738	—(CH2)2—	—NH—C(═O)—	K313	J012	T148
1739	—(CH2)2—	—NH—C(═O)—	K313	J045	T148
1740	—(CH2)2—	—NH—C(═O)—	K313	J045	T170
1741	—(CH2)2—	—NH—C(═O)—	K314	J007	T148
1742	—(CH2)2—	—NH—C(═O)—	K314	J008	T148
1743	—(CH2)2—	—NH—C(═O)—	K314	J010	T148
1744	—(CH2)2—	—NH—C(═O)—	K314	J012	T148
1745	—(CH2)2—	—NH—C(═O)—	K314	J013	T148
1746	—(CH2)2—	—NH—C(═O)—	K314	J014	T148
1747	—(CH2)2—	—NH—C(═O)—	K314	J044	T170
1748	—(CH2)2—	—NH—C(═O)—	K314	J045	T148
1749	—(CH2)2—	—NH—C(═O)—	K314	J045	T169
1750	—(CH2)2—	—NH—C(═O)—	K314	J045	T170
1751	—(CH2)2—	—NH—C(═O)—	K315	J045	T148
1752	—(CH2)2—	—NH—C(═O)—	K315	J045	T170
1753	—(CH2)2—	—NH—C(═O)—	K316	J045	T148
1754	—(CH2)2—	—NH—C(═O)—	K316	J045	T170
1755	—(CH2)2—	—NH—C(═O)—	K317	J012	T148
1756	—(CH2)2—	—NH—C(═O)—	K317	J045	T170
1757	—(CH2)2—	—NH—C(═O)—	K318	J045	T170
1758	—(CH2)2—	—NH—C(═O)—	K319	J045	T148
1759	—(CH2)2—	—NH—C(═O)—	K319	J045	T170
1760	—(CH2)2—	—NH—C(═O)—	K320	J045	T170
1761	—(CH2)2—	—NH—C(═O)—	K321	J045	T170
1762	—(CH2)2—	—NH—C(═O)—	K322	J045	T170
1763	—(CH2)2—	—NH—C(═O)—	K323	J007	T148
1764	—(CH2)2—	—NH—C(═O)—	K323	J008	T148
1765	—(CH2)2—	—NH—C(═O)—	K323	J010	T148
1766	—(CH2)2—	—NH—C(═O)—	K323	J013	T148
1767	—(CH2)2—	—NH—C(═O)—	K323	J014	T148
1768	—(CH2)2—	—NH—C(═O)—	K323	J045	T169
1769	—(CH2)2—	—NH—C(═O)—	K323	J045	T170
1770	—(CH2)2—	—NH—C(═O)—	K326	J045	T170
1771	—(CH2)2—	—NH—C(═O)—	K332	J012	T148
1772	—(CH2)2—	—NH—C(═O)—	K332	J012	T164
1773	—(CH2)2—	—NH—C(═O)—	K332	J013	T148
1774	—(CH2)2—	—NH—C(═O)—	K332	J013	T170
1775	—(CH2)2—	—NH—C(═O)—	K332	J045	T170
1776	—(CH2)2—	—NH—C(═O)—	K332	J045	T178
1777	—(CH2)2—	—NH—C(═O)—	K332	J045	T179
1778	—(CH2)2—	—NH—C(═O)—	K333	J012	T148
1779	—(CH2)2—	—NH—C(═O)—	K333	J012	T164
1780	—(CH2)2—	—NH—C(═O)—	K333	J013	T148
1781	—(CH2)2—	—NH—C(═O)—	K333	J013	T170
1782	—(CH2)2—	—NH—C(═O)—	K333	J045	T170
1783	—(CH2)2—	—NH—C(═O)—	K333	J045	T178
1784	—(CH2)2—	—NH—C(═O)—	K333	J045	T179
1785	—(CH2)2—	—NH—C(═O)—	K335	J012	T148
1786	—(CH2)2—	—NH—C(═O)—	K335	J012	T164
1787	—(CH2)2—	—NH—C(═O)—	K335	J013	T148
1788	—(CH2)2—	—NH—C(═O)—	K335	J013	T170
1789	—(CH2)2—	—NH—C(═O)—	K335	J045	T170
1790	—(CH2)2—	—NH—C(═O)—	K335	J045	T178
1791	—(CH2)2—	—NH—C(═O)—	K335	J045	T179
1792	—(CH2)2—	—NH—C(═O)—	K336	J012	T148
1793	—(CH2)2—	—NH—C(═O)—	K336	J012	T164
1794	—(CH2)2—	—NH—C(═O)—	K336	J013	T148
1795	—(CH2)2—	—NH—C(═O)—	K336	J013	T170
1796	—(CH2)2—	—NH—C(═O)—	K336	J045	T170
1797	—(CH2)2—	—NH—C(═O)—	K336	J045	T178
1798	—(CH2)2—	—NH—C(═O)—	K336	J045	T179
1799	—(CH2)2—	—NH—C(═O)—	K340	J045	T170
1800	—(CH2)2—	—NH—C(═O)—	K343	J045	T170
1801	—(CH2)2—	—NH—C(═O)—	K345	J045	T169
1802	—(CH2)2—	—NH—C(═O)—	K346	J045	T169
1803	—(CH2)2—	—NH—C(═O)—	K346	J045	T170
1804	—(CH2)2—	—NH—C(═O)—	K355	J045	T148
1805	—(CH2)2—	—NH—C(═O)—	K356	J045	T148
1806	—(CH2)2—	—NH—C(═O)—	K357	J045	T148
1807	—(CH2)2—	—NH—C(═O)—	K357	J045	T170
1808	—(CH2)2—	—NH—C(═O)—	K358	J045	T148
1809	—(CH2)2—	—NH—C(═O)—	K358	J045	T170
1810	—(CH2)2—	—NH—C(═O)—	K359	J012	T170
1811	—(CH2)2—	—NH—C(═O)—	K359	J045	T170
1812	—(CH2)2—	—NH—C(═O)—	K360	J012	T170
1813	—(CH2)2—	—NH—C(═O)—	K360	J045	T170
1814	—(CH2)2—	—NH—C(═O)—	K361	J012	T170
1815	—(CH2)2—	—NH—C(═O)—	K361	J045	T170
1816	—(CH2)2—	—NH—C(═O)—	K362	J012	T170
1817	—(CH2)2—	—NH—C(═O)—	K362	J045	T170
1818	—(CH2)2—	—NH—C(═O)—	K363	J012	T170
1819	—(CH2)2—	—NH—C(═O)—	K363	J045	T170
1820	—(CH2)2—	—NH—C(═O)—	K364	J012	T170
1821	—(CH2)2—	—NH—C(═O)—	K364	J045	T170
1822	—(CH2)2—	—NH—C(═O)—	K365	J012	T170
1823	—(CH2)2—	—NH—C(═O)—	K365	J045	T148
1824	—(CH2)2—	—NH—C(═O)—	K365	J045	T170
1825	—(CH2)2—	—NH—C(═O)—	K366	J012	T170
1826	—(CH2)2—	—NH—C(═O)—	K366	J045	T170
1827	—(CH2)2—	—NH—C(═O)—	K367	J012	T170
1828	—(CH2)2—	—NH—C(═O)—	K367	J045	T148
1829	—(CH2)2—	—NH—C(═O)—	K367	J045	T170
1830	—(CH2)2—	—NH—C(═O)—	K368	J012	T170
1831	—(CH2)2—	—NH—C(═O)—	K368	J045	T170
1832	—(CH2)2—	—NH—C(═O)—	K369	J012	T170
1833	—(CH2)2—	—NH—C(═O)—	K369	J045	T148
1834	—(CH2)2—	—NH—C(═O)—	K369	J045	T170
1835	—(CH2)2—	—NH—C(═O)—	K370	J012	T170
1836	—(CH2)2—	—NH—C(═O)—	K370	J045	T170
1837	—(CH2)2—	—NH—C(═O)—	K371	J012	T170
1838	—(CH2)2—	—NH—C(═O)—	K371	J045	T170
1839	—(CH2)2—	—NH—C(═O)—	K372	J012	T170
1840	—(CH2)2—	—NH—C(═O)—	K372	J045	T170
1841	—(CH2)2—	—NH—C(═O)—	K373	J012	T170
1842	—(CH2)2—	—NH—C(═O)—	K373	J045	T170
1843	—(CH2)2—	—NH—C(═O)—	K374	J012	T148
1844	—(CH2)2—	—NH—C(═O)—	K374	J012	T170
1845	—(CH2)2—	—NH—C(═O)—	K374	J045	T170
1846	—(CH2)2—	—NH—C(═O)—	K375	J012	T148
1847	—(CH2)2—	—NH—C(═O)—	K375	J012	T170
1848	—(CH2)2—	—NH—C(═O)—	K375	J045	T170
1849	—(CH2)2—	—NH—C(═O)—	K376	J012	T148
1850	—(CH2)2—	—NH—C(═O)—	K376	J012	T170
1851	—(CH2)2—	—NH—C(═O)—	K376	J045	T170
1852	—(CH2)2—	—NH—C(═O)—	K377	J012	T148
1853	—(CH2)2—	—NH—C(═O)—	K377	J012	T170
1854	—(CH2)2—	—NH—C(═O)—	K377	J045	T170
1855	—(CH2)2—	—NH—C(═O)—	K378	J012	T148
1856	—(CH2)2—	—NH—C(═O)—	K378	J012	T170
1857	—(CH2)2—	—NH—C(═O)—	K378	J039	T170
1858	—(CH2)2—	—NH—C(═O)—	K378	J044	T170
1859	—(CH2)2—	—NH—C(═O)—	K378	J045	T169
1860	—(CH2)2—	—NH—C(═O)—	K378	J045	T170
1861	—(CH2)2—	—NH—C(═O)—	K379	J012	T148
1862	—(CH2)2—	—NH—C(═O)—	K379	J012	T170
1863	—(CH2)2—	—NH—C(═O)—	K379	J045	T169
1864	—(CH2)2—	—NH—C(═O)—	K379	J045	T170
1865	—(CH2)2—	—NH—C(═O)—	K380	J012	T148
1866	—(CH2)2—	—NH—C(═O)—	K380	J012	T170
1867	—(CH2)2—	—NH—C(═O)—	K380	J045	T170
1868	—(CH2)2—	—NH—C(═O)—	K381	J012	T148
1869	—(CH2)2—	—NH—C(═O)—	K381	J012	T170
1870	—(CH2)2—	—NH—C(═O)—	K381	J045	T169
1871	—(CH2)2—	—NH—C(═O)—	K381	J045	T170
1872	—(CH2)2—	—NH—C(═O)—	K382	J007	T148
1873	—(CH2)2—	—NH—C(═O)—	K382	J008	T148
1874	—(CH2)2—	—NH—C(═O)—	K382	J010	T148
1875	—(CH2)2—	—NH—C(═O)—	K382	J012	T148
1876	—(CH2)2—	—NH—C(═O)—	K382	J012	T170
1877	—(CH2)2—	—NH—C(═O)—	K382	J013	T148
1878	—(CH2)2—	—NH—C(═O)—	K382	J014	T148
1879	—(CH2)2—	—NH—C(═O)—	K382	J039	T170
1880	—(CH2)2—	—NH—C(═O)—	K382	J044	T170
1881	—(CH2)2—	—NH—C(═O)—	K382	J045	T169
1882	—(CH2)2—	—NH—C(═O)—	K382	J045	T170
1883	—(CH2)2—	—NH—C(═O)—	K383	J012	T170
1884	—(CH2)2—	—NH—C(═O)—	K383	J045	T170
1885	—(CH2)2—	—NH—C(═O)—	K384	J012	T148
1886	—(CH2)2—	—NH—C(═O)—	K384	J012	T170
1887	—(CH2)2—	—NH—C(═O)—	K384	J039	T170
1888	—(CH2)2—	—NH—C(═O)—	K384	J044	T170
1889	—(CH2)2—	—NH—C(═O)—	K384	J045	T169
1890	—(CH2)2—	—NH—C(═O)—	K384	J045	T170
1891	—(CH2)2—	—NH—C(═O)—	K385	J012	T148
1892	—(CH2)2—	—NH—C(═O)—	K385	J012	T170
1893	—(CH2)2—	—NH—C(═O)—	K385	J045	T169
1894	—(CH2)2—	—NH—C(═O)—	K385	J045	T170
1895	—(CH2)2—	—NH—C(═O)—	K386	J012	T148
1896	—(CH2)2—	—NH—C(═O)—	K386	J039	T170
1897	—(CH2)2—	—NH—C(═O)—	K386	J044	T170
1898	—(CH2)2—	—NH—C(═O)—	K386	J045	T170
1899	—(CH2)2—	—NH—C(═O)—	K387	J012	T148
1900	—(CH2)2—	—NH—C(═O)—	K387	J045	T170
1901	—(CH2)2—	—NH—C(═O)—	K388	J012	T148
1902	—(CH2)2—	—NH—C(═O)—	K388	J039	T170
1903	—(CH2)2—	—NH—C(═O)—	K388	J044	T170
1904	—(CH2)2—	—NH—C(═O)—	K388	J045	T170
1905	—(CH2)2—	—NH—C(═O)—	K389	J012	T148
1906	—(CH2)2—	—NH—C(═O)—	K389	J045	T170
1907	—(CH2)2—	—NH—C(═O)—	K390	J012	T148
1908	—(CH2)2—	—NH—C(═O)—	K390	J045	T170
1909	—(CH2)2—	—NH—C(═O)—	K391	J012	T148
1910	—(CH2)2—	—NH—C(═O)—	K391	J045	T170
1911	—(CH2)2—	—NH—C(═O)—	K392	J012	T148
1912	—(CH2)2—	—NH—C(═O)—	K392	J045	T170
1913	—(CH2)2—	—NH—C(═O)—	K393	J012	T148
1914	—(CH2)2—	—NH—C(═O)—	K393	J045	T170
1915	—(CH2)2—	—NH—C(═O)—	K394	J012	T148
1916	—(CH2)2—	—NH—C(═O)—	K394	J045	T170
1917	—(CH2)2—	—NH—C(═O)—	K398	J012	T148
1918	—(CH2)2—	—NH—C(═O)—	K399	J010	T148
1919	—(CH2)2—	—NH—C(═O)—	K399	J010	T170
1920	—(CH2)2—	—NH—C(═O)—	K399	J012	T148
1921	—(CH2)2—	—NH—C(═O)—	K399	J013	T148
1922	—(CH2)2—	—NH—C(═O)—	K399	J013	T170
1923	—(CH2)2—	—NH—C(═O)—	K399	J044	T170
1924	—(CH2)2—	—NH—C(═O)—	K399	J045	T170
1925	—(CH2)2—	—NH—C(═O)—	K399	J146	T148
1926	—(CH2)2—	—NH—C(═O)—	K399	J147	T148
1927	—(CH2)2—	—NH—C(═O)—	K399	J150	T148
1928	—(CH2)2—	—NH—C(═O)—	K399	J150	T170
1929	—(CH2)2—	—NH—C(═O)—	K399	J151	T148
1930	—(CH2)2—	—NH—C(═O)—	K399	J159	T148
1931	—(CH2)2—	—NH—C(═O)—	K399	J159	T170
1932	—(CH2)2—	—NH—C(═O)—	K400	J012	T148
1933	—(CH2)2—	—NH—C(═O)—	K400	J013	T170
1934	—(CH2)2—	—NH—C(═O)—	K400	J045	T170
1935	—(CH2)2—	—NH—C(═O)—	K400	J151	T148
1936	—(CH2)2—	—NH—C(═O)—	K400	J151	T170
1937	—(CH2)2—	—NH—C(═O)—	K401	J012	T148
1938	—(CH2)2—	—NH—C(═O)—	K401	J045	T170
1939	—(CH2)2—	—NH—C(═O)—	K402	J012	T148
1940	—(CH2)2—	—NH—C(═O)—	K402	J045	T170
1941	—(CH2)2—	—NH—C(═O)—	K402	J151	T170
1942	—(CH2)2—	—NH—C(═O)—	K402	J159	T148
1943	—(CH2)2—	—NH—C(═O)—	K402	J159	T170
1944	—(CH2)2—	—NH—C(═O)—	K403	J012	T148
1945	—(CH2)2—	—NH—C(═O)—	K403	J013	T148
1946	—(CH2)2—	—NH—C(═O)—	K403	J013	T170
1947	—(CH2)2—	—NH—C(═O)—	K403	J044	T170
1948	—(CH2)2—	—NH—C(═O)—	K403	J045	T170
1949	—(CH2)2—	—NH—C(═O)—	K403	J151	T148
1950	—(CH2)2—	—NH—C(═O)—	K403	J151	T170
1951	—(CH2)2—	—NH—C(═O)—	K403	J158	T170
1952	—(CH2)2—	—NH—C(═O)—	K404	J012	T148
1953	—(CH2)2—	—NH—C(═O)—	K405	J012	T148
1954	—(CH2)2—	—NH—C(═O)—	K406	J012	T148
1955	—(CH2)2—	—NH—C(═O)—	K406	J045	T170
1956	—(CH2)2—	—NH—C(═O)—	K407	J012	T148
1957	—(CH2)2—	—NH—C(═O)—	K407	J013	T148
1958	—(CH2)2—	—NH—C(═O)—	K407	J013	T170
1959	—(CH2)2—	—NH—C(═O)—	K407	J044	T170
1960	—(CH2)2—	—NH—C(═O)—	K407	J045	T170
1961	—(CH2)2—	—NH—C(═O)—	K408	J012	T148
1962	—(CH2)2—	—NH—C(═O)—	K409	J012	T148
1963	—(CH2)2—	—NH—C(═O)—	K409	J045	T170
1964	—(CH2)2—	—NH—C(═O)—	K410	J012	T148
1965	—(CH2)2—	—NH—C(═O)—	K411	J012	T148
1966	—(CH2)2—	—NH—C(═O)—	K411	J045	T170
1967	—(CH2)2—	—NH—C(═O)—	K412	J012	T148
1968	—(CH2)2—	—NH—C(═O)—	K413	J012	T148
1969	—(CH2)2—	—NH—C(═O)—	K414	J012	T148
1970	—(CH2)2—	—NH—C(═O)—	K414	J044	T170
1971	—(CH2)2—	—NH—C(═O)—	K414	J045	T170
1972	—(CH2)2—	—NH—C(═O)—	K415	J012	T148
1973	—(CH2)2—	—NH—C(═O)—	K415	J013	T148
1974	—(CH2)2—	—NH—C(═O)—	K415	J013	T170
1975	—(CH2)2—	—NH—C(═O)—	K415	J044	T170
1976	—(CH2)2—	—NH—C(═O)—	K415	J045	T170
1977	—(CH2)2—	—NH—C(═O)—	K415	J151	T148
1978	—(CH2)2—	—NH—C(═O)—	K415	J151	T170
1979	—(CH2)2—	—NH—C(═O)—	K415	J158	T170
1980	—(CH2)2—	—NH—C(═O)—	K416	J012	T148
1981	—(CH2)2—	—NH—C(═O)—	K417	J012	T148
1982	—(CH2)2—	—NH—C(═O)—	K418	J012	T148
1983	—(CH2)2—	—NH—C(═O)—	K419	J012	T148
1984	—(CH2)2—	—NH—C(═O)—	K419	J045	T170
1985	—(CH2)2—	—NH—C(═O)—	K420	J012	T148
1986	—(CH2)2—	—NH—C(═O)—	K420	J013	T148
1987	—(CH2)2—	—NH—C(═O)—	K420	J013	T170
1988	—(CH2)2—	—NH—C(═O)—	K420	J044	T170
1989	—(CH2)2—	—NH—C(═O)—	K420	J045	T148
1990	—(CH2)2—	—NH—C(═O)—	K420	J045	T170
1991	—(CH2)2—	—NH—C(═O)—	K420	J149	T148
1992	—(CH2)2—	—NH—C(═O)—	K420	J150	T148
1993	—(CH2)2—	—NH—C(═O)—	K420	J150	T170
1994	—(CH2)2—	—NH—C(═O)—	K420	J151	T148
1995	—(CH2)2—	—NH—C(═O)—	K420	J151	T170
1996	—(CH2)2—	—NH—C(═O)—	K420	J158	T170
1997	—(CH2)2—	—NH—C(═O)—	K421	J012	T148
1998	—(CH2)2—	—NH—C(═O)—	K422	J012	T148
1999	—(CH2)2—	—NH—C(═O)—	K423	J012	T148
2000	—(CH2)2—	—NH—C(═O)—	K424	J012	T148
2001	—(CH2)2—	—NH—C(═O)—	K425	J012	T148
2002	—(CH2)2—	—NH—C(═O)—	K426	J012	T148
2003	—(CH2)2—	—NH—C(═O)—	K200	J022	T170
2004	—(CH2)2—	—NH—C(═O)—	K357	J012	T148
2005	—(CH2)2—	—NH—C(═O)—NH—	K005	J045	T148
2006	—(CH2)2—	—NH—C(═O)—NH—	K008	J045	T148
2007	—(CH2)2—	—NH—C(═O)—NH—	K023	J012	T148
2008	—(CH2)2—	—NH—C(═O)—NH—	K033	J012	T148
2009	—(CH2)2—	—NH—C(═O)—NH—	K077	J045	T148
2010	—(CH2)2—	—NH—C(═O)—NH—	K102	J045	T148
2011	—(CH2)2—	—NH—C(═O)—NH—	K102	J045	T170
2012	—(CH2)2—	—NH—C(═O)—NH—	K106	J045	T148
2013	—(CH2)2—	—NH—C(═O)—NH—	K336	J012	T148
2014	—(CH2)2—	—NH—C(═O)—NH—	K204	J045	T148
2015	—(CH2)2—	—NH—C(═O)—NH—	K204	J045	T170
2016	—(CH2)2—	—NH—C(═O)—NH—	K223	J045	T148
2017	—(CH2)2—	—NH—C(═O)—NH—	K230	J012	T148
2018	—(CH2)2—	—NH—C(═O)—NH—	K231	J012	T148
2019	—(CH2)2—	—NH—C(═O)—NH—	K248	J045	T148
2020	—(CH2)2—	—NH—C(═O)—NH—	K249	J045	T148
2021	—(CH2)2—	—NH—C(═O)—NH—	K250	J045	T148
2022	—(CH2)2—	—NH—C(═O)—NH—	K278	J012	T148
2023	—(CH2)2—	—NH—C(═O)—NH—	K277	J045	T148
2024	—(CH2)2—	—NH—C(═O)—NH—	K277	J045	T170
2025	—(CH2)2—	—NH—C(═O)—NH—	K278	J045	T148
2026	—(CH2)2—	—NH—C(═O)—NH—	K278	J045	T170
2027	—(CH2)2—	—NH—C(═O)—NH—	K279	J045	T148
2028	—(CH2)2—	—NH—C(═O)—NH—	K286	J045	T148
2029	—(CH2)2—	—NH—C(═O)—NH—	K324	J045	T148
2030	—(CH2)2—	—NH—C(═O)—NH—	K324	J045	T170
2031	—(CH2)2—	—NH—C(═O)—NH—	K325	J012	T148
2032	—(CH2)2—	—NH—C(═O)—NH—	K325	J045	T148
2033	—(CH2)2—	—NH—C(═O)—NH—	K325	J045	T170
2034	—(CH2)2—	—NH—C(═O)—NH—	K326	J045	T148
2035	—(CH2)2—	—NH—C(═O)—NH—	K326	J045	T169
2036	—(CH2)2—	—NH—C(═O)—NH—	K326	J045	T170
2037	—(CH2)2—	—NH—C(═O)—NH—	K327	J045	T170
2038	—(CH2)2—	—NH—C(═O)—NH—	K328	J045	T170
2039	—(CH2)2—	—NH—C(═O)—NH—	K329	J045	T170
2040	—(CH2)2—	—NH—C(═O)—NH—	K330	J012	T148
2041	—(CH2)2—	—NH—C(═O)—NH—	K330	J045	T170
2042	—(CH2)2—	—NH—C(═O)—NH—	K331	J012	T148
2043	—(CH2)2—	—NH—C(═O)—NH—	K331	J045	T170
2044	—(CH2)2—	—NH—C(═O)—NH—	K332	J045	T169
2045	—(CH2)2—	—NH—C(═O)—NH—	K332	J045	T170
2046	—(CH2)2—	—NH—C(═O)—NH—	K333	J012	T148
2047	—(CH2)2—	—NH—C(═O)—NH—	K333	J044	T170
2048	—(CH2)2—	—NH—C(═O)—NH—	K333	J045	T169
2049	—(CH2)2—	—NH—C(═O)—NH—	K333	J045	T170
2050	—(CH2)2—	—NH—C(═O)—NH—	K334	J045	T170
2051	—(CH2)2—	—NH—C(═O)—NH—	K335	J044	T170
2052	—(CH2)2—	—NH—C(═O)—NH—	K335	J045	T148
2053	—(CH2)2—	—NH—C(═O)—NH—	K335	J045	T170
2054	—(CH2)2—	—NH—C(═O)—NH—	K336	J012	T170
2055	—(CH2)2—	—NH—C(═O)—NH—	K336	J044	T170
2056	—(CH2)2—	—NH—C(═O)—NH—	K336	J045	T148
2057	—(CH2)2—	—NH—C(═O)—NH—	K336	J045	T169
2058	—(CH2)2—	—NH—C(═O)—NH—	K336	J045	T170
2059	—(CH2)2—	—NH—C(═O)—NH—	K337	J045	T170
2060	—(CH2)2—	—NH—C(═O)—NH—	K338	J045	T148
2061	—(CH2)2—	—NH—C(═O)—NH—	K338	J045	T170
2062	—(CH2)2—	—NH—C(═O)—NH—	K339	J045	T148
2063	—(CH2)2—	—NH—C(═O)—NH—	K339	J045	T170
2064	—(CH2)2—	—NH—C(═O)—NH—	K340	J012	T148
2065	—(CH2)2—	—NH—C(═O)—NH—	K340	J045	T148
2066	—(CH2)2—	—NH—C(═O)—NH—	K340	J045	T169
2067	—(CH2)2—	—NH—C(═O)—NH—	K340	J045	T170
2068	—(CH2)2—	—NH—C(═O)—NH—	K341	J045	T148
2069	—(CH2)2—	—NH—C(═O)—NH—	K341	J045	T170
2070	—(CH2)2—	—NH—C(═O)—NH—	K342	J045	T148
2071	—(CH2)2—	—NH—C(═O)—NH—	K342	J045	T170
2072	—(CH2)2—	—NH—C(═O)—NH—	K343	J045	T148
2073	—(CH2)2—	—NH—C(═O)—NH—	K343	J045	T170
2074	—(CH2)2—	—NH—C(═O)—NH—	K344	J045	T170
2075	—(CH2)2—	—NH—C(═O)—NH—	K345	J045	T170
2076	—(CH2)2—	—NH—C(═O)—NH—	K346	J045	T170
2077	—(CH2)2—	—NH—C(═O)—NH—	K347	J045	T170
2078	—(CH2)2—	—NH—C(═O)—NH—	K348	J045	T148
2079	—(CH2)2—	—NH—C(═O)—NH—	K348	J045	T170
2080	—(CH2)2—	—NH—C(═O)—NH—	K349	J045	T170
2081	—(CH2)2—	—NH—C(═O)—NH—	K350	J045	T148
2082	—(CH2)2—	—NH—C(═O)—NH—	K350	J045	T170
2083	—(CH2)2—	—NH—C(═O)—NH—	K351	J045	T148
2084	—(CH2)2—	—NH—C(═O)—NH—	K351	J045	T170
2085	—(CH2)2—	—NH—C(═O)—NH—	K352	J045	T148
2086	—(CH2)2—	—NH—C(═O)—NH—	K352	J045	T170
2087	—(CH2)2—	—NH—C(═O)—NH—	K353	J045	T148
2088	—(CH2)2—	—NH—C(═O)—NH—	K353	J045	T170
2089	—(CH2)2—	—NH—C(═O)—NH—	K354	J045	T148
2090	—(CH2)2—	—NH—C(═O)—NH—	K354	J045	T170
2091	—(CH2)2—	—NH—C(═O)—NH—	K355	J045	T170
2092	—(CH2)2—	—NH—C(═O)—NH—	K356	J045	T170
2093	—(CH2)2—	—NH—C(═O)—NH—	K359	J045	T148
2094	—(CH2)2—	—NH—C(═O)—NH—	K360	J045	T148
2095	—(CH2)2—	—NH—C(═O)—NH—	K362	J045	T148
2096	—(CH2)2—	—NH—C(═O)—NH—	K361	J045	T148
2097	—(CH2)2—	—NH—C(═O)—NH—	K362	J045	T170
2098	—(CH2)2—	—NH—C(═O)—NH—	K364	J045	T170
2099	—(CH2)2—	—NH—C(═O)—NH—	K370	J045	T148
2100	—(CH2)2—	—NH—C(═O)—NH—	K371	J045	T148
2101	—(CH2)2—	—NH—C(═O)—NH—	K373	J045	T148
2102	—(CH2)2—	—NH—C(═O)—NH—	K431	J045	T170
2103	—(CH2)2—	—NH—C(═O)—NH—	K395	J012	T148
2104	—(CH2)2—	—NH—C(═O)—NH—	K395	J045	T170
2105	—(CH2)2—	—NH—C(═O)—NH—	K396	J012	T148
2106	—(CH2)2—	—NH—C(═O)—NH—	K396	J045	T170
2107	—(CH2)2—	—NH—C(═O)—NH—	K397	J012	T148
2108	—(CH2)2—	—NH—C(═O)—NH—	K397	J045	T170
2109	—(CH2)2—	—NH—C(═O)—	K241	J045	T148
2110	—(CH2)2—	—NH—C(═O)—O—	K005	J001	T148
2111	—(CH2)2—	—NH—C(═O)—O—	K005	J007	T148
2112	—(CH2)2—	—NH—C(═O)—O—	K005	J008	T148
2113	—(CH2)2—	—NH—C(═O)—O—	K005	J009	T170
2114	—(CH2)2—	—NH—C(═O)—O—	K005	J010	T148
2115	—(CH2)2—	—NH—C(═O)—O—	K005	J011	T170
2116	—(CH2)2—	—NH—C(═O)—O—	K005	J012	T170
2117	—(CH2)2—	—NH—C(═O)—O—	K005	J013	T148
2118	—(CH2)2—	—NH—C(═O)—O—	K005	J014	T148
2119	—(CH2)2—	—NH—C(═O)—O—	K005	J015	T170
2120	—(CH2)2—	—NH—C(═O)—O—	K005	J026	T001
2121	—(CH2)2—	—NH—C(═O)—O—	K005	J026	T148
2122	—(CH2)2—	—NH—C(═O)—O—	K005	J026	T170
2123	—(CH2)2—	—NH—C(═O)—O—	K005	J037	T170
2124	—(CH2)2—	—NH—C(═O)—O—	K005	J039	T170
2125	—(CH2)2—	—NH—C(═O)—O—	K005	J043	T170
2126	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T072
2127	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T074
2128	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T180
2129	—(CH2)2—	—NH—C(═O)—O—	K005	J047	T170
2130	—(CH2)2—	—NH—C(═O)—O—	K005	J079	T170
2131	—(CH2)2—	—NH—C(═O)—O—	K005	J080	T148
2132	—(CH2)2—	—NH—C(═O)—O—	K005	J081	T148
2133	—(CH2)2—	—NH—C(═O)—O—	K005	J082	T148
2134	—(CH2)2—	—NH—C(═O)—O—	K005	J090	T148
2135	—(CH2)2—	—NH—C(═O)—O—	K005	J092	T148
2136	—(CH2)2—	—NH—C(═O)—O—	K005	J103	T170
2137	—(CH2)2—	—NH—C(═O)—O—	K005	J104	T170
2138	—(CH2)2—	—NH—C(═O)—O—	K005	J105	T170
2139	—(CH2)2—	—NH—C(═O)—O—	K005	J106	T170
2140	—(CH2)2—	—NH—C(═O)—O—	K005	J107	T170
2141	—(CH2)2—	—NH—C(═O)—O—	K005	J140	T001
2142	—(CH2)2—	—NH—C(═O)—O—	K005	J140	T148
2143	—(CH2)2—	—NH—C(═O)—O—	K005	J140	T170
2144	—(CH2)2—	—NH—C(═O)—O—	K005	J144	T148
2145	—(CH2)2—	—NH—C(═O)—O—	K005	J146	T148
2146	—(CH2)2—	—NH—C(═O)—O—	K199	J045	T148
2147	—(CH2)2—	—NH—C(═O)—O—	K223	J045	T148
2148	—(CH2)2—	—NH—C(═O)—O—	K198	J045	T148
2149	—(CH2)2—	—NH—S(═O)2—	K200	J012	T148
2150	—(CH2)2—	—NH—S(═O)2—	K200	J044	T170
2151	—(CH2)2—	—NH—S(═O)2—	K200	J045	T170
2152	—(CH2)2—	—NH—S(═O)2—	K223	J012	T148
2153	—(CH2)2—	—NH—S(═O)2—	K223	J044	T170
2154	—(CH2)2—	—NH—S(═O)2—	K230	J044	T170
2155	—(CH2)2—	—NH—S(═O)2—	K230	J045	T170
2156	—(CH2)2—	—NH—S(═O)2—	K231	J044	T170
2157	—(CH2)2—	—NH—S(═O)2—	K231	J045	T170
2158	—(CH2)3—	—C(═O)—	K108	J001	T148
2159	—(CH2)3—	—C(═O)—	K108	J022	T170
2160	—(CH2)3—	—C(═O)—	K109	J029	T170
2161	—(CH2)3—	—C(═O)—	K112	J012	T148
2162	—(CH2)3—	—C(═O)—	K112	J012	T170
2163	—(CH2)3—	—C(═O)—	K112	J037	T170
2164	—(CH2)3—	—C(═O)—	K112	J043	T170
2165	—(CH2)3—	—C(═O)—	K112	J138	T148
2166	—(CH2)3—	—C(═O)—	K112	J138	T170
2167	—(CH2)3—	—C(═O)—	K112	J144	T148
2168	—(CH2)3—	—C(═O)—	K112	J144	T164
2169	—(CH2)3—	—C(═O)—	K112	J144	T169
2170	—(CH2)3—	—C(═O)—	K112	J144	T170
2171	—(CH2)3—	—C(═O)—	K116	J012	T148
2172	—(CH2)3—	—C(═O)—	K121	J043	T170
2173	—(CH2)3—	—C(═O)—	K129	J012	T148
2174	—(CH2)3—	—C(═O)—	K136	J044	T170
2175	—(CH2)3—	—C(═O)—	K137	J012	T148
2176	—(CH2)3—	—C(═O)—	K137	J012	T170
2177	—(CH2)3—	—C(═O)—	K137	J045	T170
2178	—(CH2)3—	—C(═O)—	K138	J079	T170
2179	—(CH2)3—	—C(═O)—	K139	J012	T148
2180	—(CH2)3—	—C(═O)—	K142	J012	T148
2181	—(CH2)3—	—C(═O)—	K143	J012	T148
2182	—(CH2)3—	—C(═O)—	K144	J012	T148
2183	—(CH2)3—	—C(═O)—	K144	J043	T148
2184	—(CH2)3—	—C(═O)—	K144	J043	T170
2185	—(CH2)3—	—C(═O)—	K144	J138	T148
2186	—(CH2)3—	—C(═O)—	K144	J138	T170
2187	—(CH2)3—	—C(═O)—	K144	J144	T148
2188	—(CH2)3—	—C(═O)—	K144	J144	T170
2189	—(CH2)3—	—C(═O)—	K147	J012	T148
2190	—(CH2)3—	—C(═O)—	K147	J138	T170
2191	—(CH2)3—	—C(═O)—	K148	J012	T148
2192	—(CH2)3—	—C(═O)—	K148	J139	T170
2193	—(CH2)3—	—C(═O)—	K150	J012	T148
2194	—(CH2)3—	—C(═O)—	K154	J012	T148
2195	—(CH2)3—	—C(═O)—	K166	J012	T148
2196	—(CH2)3—	—C(═O)—	K166	J144	T170
2197	—(CH2)3—	—C(═O)—	K170	J007	T170
2198	—(CH2)3—	—C(═O)—	K172	J012	T170
2199	—(CH2)3—	—C(═O)—	K237	J012	T148
2200	—(CH2)3—	—C(═O)—	K391	J144	T170
2201	—(CH2)3—	—C(═O)—NH—	K004	J012	T148
2202	—(CH2)3—	—C(═O)—NH—	K009	J001	T148
2203	—(CH2)3—	—C(═O)—NH—	K009	J007	T148
2204	—(CH2)3—	—C(═O)—NH—	K009	J007	T164
2205	—(CH2)3—	—C(═O)—NH—	K009	J007	T169
2206	—(CH2)3—	—C(═O)—NH—	K009	J007	T170
2207	—(CH2)3—	—C(═O)—NH—	K009	J012	T148
2208	—(CH2)3—	—C(═O)—NH—	K009	J037	T170
2209	—(CH2)3—	—C(═O)—NH—	K012	J001	T148
2210	—(CH2)3—	—C(═O)—NH—	K013	J012	T148
2211	—(CH2)3—	—C(═O)—NH—	K013	J012	T170
2212	—(CH2)3—	—C(═O)—NH—	K023	J012	T148
2213	—(CH2)3—	—C(═O)—NH—	K023	J029	T148
2214	—(CH2)3—	—C(═O)—NH—	K023	J029	T164
2215	—(CH2)3—	—C(═O)—NH—	K023	J029	T169
2216	—(CH2)3—	—C(═O)—NH—	K023	J029	T170
2217	—(CH2)3—	—C(═O)—NH—	K023	J043	T170
2218	—(CH2)3—	—C(═O)—NH—	K029	J012	T148
2219	—(CH2)3—	—C(═O)—NH—	K029	J044	T148
2220	—(CH2)3—	—C(═O)—NH—	K029	J044	T164
2221	—(CH2)3—	—C(═O)—NH—	K029	J044	T169
2222	—(CH2)3—	—C(═O)—NH—	K029	J044	T170
2223	—(CH2)3—	—C(═O)—NH—	K029	J045	T170
2224	—(CH2)3—	—C(═O)—NH—	K033	J012	T148
2225	—(CH2)3—	—C(═O)—NH—	K033	J043	T148
2226	—(CH2)3—	—C(═O)—NH—	K033	J043	T164
2227	—(CH2)3—	—C(═O)—NH—	K033	J043	T169
2228	—(CH2)3—	—C(═O)—NH—	K033	J043	T170
2229	—(CH2)3—	—C(═O)—NH—	K033	J044	T170
2230	—(CH2)3—	—C(═O)—NH—	K034	J012	T148
2231	—(CH2)3—	—C(═O)—NH—	K034	J045	T148
2232	—(CH2)3—	—C(═O)—NH—	K034	J045	T164
2233	—(CH2)3—	—C(═O)—NH—	K034	J045	T169
2234	—(CH2)3—	—C(═O)—NH—	K034	J045	T170
2235	—(CH2)3—	—C(═O)—NH—	K034	J079	T170
2236	—(CH2)3—	—C(═O)—NH—	K077	J138	T170
2237	—(CH2)3—	—C(═O)—NH—	K078	J139	T170
2238	—(CH2)3—	—C(═O)—NH—	K101	J144	T170
2239	—(CH2)3—	—C(═O)—NH—	K102	J007	T170
2240	—(CH2)3—	—C(═O)—NH—	K102	J012	T148
2241	—(CH2)3—	—C(═O)—NH—	K102	J012	T170
2242	—(CH2)3—	—C(═O)—NH—	K102	J079	T148
2243	—(CH2)3—	—C(═O)—NH—	K102	J079	T164
2244	—(CH2)3—	—C(═O)—NH—	K102	J079	T169
2245	—(CH2)3—	—C(═O)—NH—	K102	J079	T170
2246	—(CH2)3—	—C(═O)—NH—	K103	J012	T148
2247	—(CH2)3—	—C(═O)—NH—	K103	J138	T148
2248	—(CH2)3—	—C(═O)—NH—	K103	J138	T164
2249	—(CH2)3—	—C(═O)—NH—	K103	J138	T169
2250	—(CH2)3—	—C(═O)—NH—	K103	J138	T170
2251	—(CH2)3—	—C(═O)—NH—	K104	J012	T148
2252	—(CH2)3—	—C(═O)—NH—	K104	J012	T170
2253	—(CH2)3—	—C(═O)—NH—	K104	J139	T148
2254	—(CH2)3—	—C(═O)—NH—	K104	J139	T164
2255	—(CH2)3—	—C(═O)—NH—	K104	J139	T169
2256	—(CH2)3—	—C(═O)—NH—	K104	J139	T170
2257	—(CH2)3—	—C(═O)—NH—	K108	J012	T148
2258	—(CH2)3—	—C(═O)—NH—	K198	J012	T148
2259	—(CH2)3—	—C(═O)—NH—	K198	J022	T170
2260	—(CH2)3—	—C(═O)—NH—	K200	J012	T148
2261	—(CH2)3—	—C(═O)—NH—	K200	J029	T170
2262	—(CH2)3—	—C(═O)—NH—	K201	J012	T148
2263	—(CH2)3—	—C(═O)—NH—	K201	J037	T170
2264	—(CH2)3—	—C(═O)—NH—	K204	J002	T148
2265	—(CH2)3—	—C(═O)—NH—	K204	J012	T148
2266	—(CH2)3—	—C(═O)—NH—	K204	J012	T170
2267	—(CH2)3—	—C(═O)—NH—	K204	J043	T148
2268	—(CH2)3—	—C(═O)—NH—	K204	J043	T170
2269	—(CH2)3—	—C(═O)—NH—	K204	J138	T170
2270	—(CH2)3—	—C(═O)—NH—	K204	J139	T148
2271	—(CH2)3—	—C(═O)—NH—	K204	J144	T148
2272	—(CH2)3—	—C(═O)—NH—	K204	J144	T170
2273	—(CH2)3—	—C(═O)—NH—	K215	J012	T148
2274	—(CH2)3—	—C(═O)—NH—	K216	J007	T170
2275	—(CH2)3—	—C(═O)—NH—	K216	J012	T148
2276	—(CH2)3—	—C(═O)—NH—	K216	J012	T164
2277	—(CH2)3—	—C(═O)—NH—	K216	J012	T170
2278	—(CH2)3—	—C(═O)—NH—	K216	J022	T170
2279	—(CH2)3—	—C(═O)—NH—	K216	J029	T170
2280	—(CH2)3—	—C(═O)—NH—	K216	J037	T170
2281	—(CH2)3—	—C(═O)—NH—	K216	J043	T148
2282	—(CH2)3—	—C(═O)—NH—	K216	J043	T170
2283	—(CH2)3—	—C(═O)—NH—	K216	J044	T169
2284	—(CH2)3—	—C(═O)—NH—	K216	J044	T170
2285	—(CH2)3—	—C(═O)—NH—	K216	J045	T170
2286	—(CH2)3—	—C(═O)—NH—	K216	J079	T170
2287	—(CH2)3—	—C(═O)—NH—	K216	J138	T148
2288	—(CH2)3—	—C(═O)—NH—	K216	J138	T170
2289	—(CH2)3—	—C(═O)—NH—	K216	J139	T170
2290	—(CH2)3—	—C(═O)—NH—	K216	J144	T148
2291	—(CH2)3—	—C(═O)—NH—	K216	J144	T170
2292	—(CH2)3—	—C(═O)—NH—	K223	J001	T148
2293	—(CH2)3—	—C(═O)—NH—	K223	J045	T170
2294	—(CH2)3—	—C(═O)—NH—	K224	J079	T170
2295	—(CH2)3—	—C(═O)—NH—	K225	J138	T170
2296	—(CH2)3—	—C(═O)—NH—	K229	J012	T148
2297	—(CH2)3—	—C(═O)—NH—	K229	J139	T170
2298	—(CH2)3—	—C(═O)—NH—	K234	J012	T148
2299	—(CH2)3—	—C(═O)—NH—	K198	J001	T148
2300	—(CH2)3—	—C(═O)—NH—	K244	J001	T148
2301	—(CH2)3—	—C(═O)—NH—	K246	J001	T148
2302	—(CH2)3—	—C(═O)—NH—	K280	J012	T148
2303	—(CH2)3—	—C(═O)—NH—	K293	J144	T170
2304	—(CH2)3—	—C(═O)—NH—	K323	J007	T170
2305	—(CH2)3—	—C(═O)—NH—	K324	J012	T148
2306	—(CH2)3—	—C(═O)—NH—	K324	J012	T170
2307	—(CH2)3—	—C(═O)—NH—	K325	J022	T170
2308	—(CH2)3—	—C(═O)—NH—	K326	J029	T170
2309	—(CH2)3—	—C(═O)—NH—	K327	J037	T170
2310	—(CH2)3—	—C(═O)—NH—	K333	J007	T170
2311	—(CH2)3—	—C(═O)—NH—	K333	J012	T148
2312	—(CH2)3—	—C(═O)—NH—	K333	J012	T170
2313	—(CH2)3—	—C(═O)—NH—	K333	J022	T170
2314	—(CH2)3—	—C(═O)—NH—	K333	J029	T170
2315	—(CH2)3—	—C(═O)—NH—	K333	J037	T170
2316	—(CH2)3—	—C(═O)—NH—	K333	J043	T170
2317	—(CH2)3—	—C(═O)—NH—	K333	J044	T170
2318	—(CH2)3—	—C(═O)—NH—	K333	J045	T170
2319	—(CH2)3—	—C(═O)—NH—	K333	J079	T170
2320	—(CH2)3—	—C(═O)—NH—	K333	J138	T170
2321	—(CH2)3—	—C(═O)—NH—	K333	J139	T170
2322	—(CH2)3—	—C(═O)—NH—	K333	J144	T170
2323	—(CH2)3—	—C(═O)—NH—	K334	J043	T170
2324	—(CH2)3—	—C(═O)—NH—	K335	J044	T170
2325	—(CH2)3—	—C(═O)—NH—	K336	J012	T148
2326	—(CH2)3—	—C(═O)—NH—	K340	J045	T170
2327	—(CH2)3—	—C(═O)—NH—	K343	J012	T148
2328	—(CH2)3—	—C(═O)—NH—	K343	J079	T170
2329	—(CH2)3—	—C(═O)—NH—	K344	J012	T148
2330	—(CH2)3—	—C(═O)—NH—	K346	J007	T170
2331	—(CH2)3—	—C(═O)—NH—	K346	J012	T148
2332	—(CH2)3—	—C(═O)—NH—	K346	J012	T170
2333	—(CH2)3—	—C(═O)—NH—	K346	J022	T170
2334	—(CH2)3—	—C(═O)—NH—	K346	J029	T170
2335	—(CH2)3—	—C(═O)—NH—	K346	J037	T170
2336	—(CH2)3—	—C(═O)—NH—	K346	J043	T148
2337	—(CH2)3—	—C(═O)—NH—	K346	J043	T170
2338	—(CH2)3—	—C(═O)—NH—	K346	J044	T170
2339	—(CH2)3—	—C(═O)—NH—	K346	J045	T170
2340	—(CH2)3—	—C(═O)—NH—	K346	J079	T170
2341	—(CH2)3—	—C(═O)—NH—	K346	J080/J081	T148
2342	—(CH2)3—	—C(═O)—NH—	K346	J090	T148
2343	—(CH2)3—	—C(═O)—NH—	K346	J100	T148
2344	—(CH2)3—	—C(═O)—NH—	K346	J138	T148
2345	—(CH2)3—	—C(═O)—NH—	K346	J138	T170
2346	—(CH2)3—	—C(═O)—NH—	K346	J139	T170
2347	—(CH2)3—	—C(═O)—NH—	K346	J144	T148
2348	—(CH2)3—	—C(═O)—NH—	K346	J144	T170
2349	—(CH2)3—	—C(═O)—NH—	K347	J138	T170
2350	—(CH2)3—	—C(═O)—NH—	K353	J012	T148
2351	—(CH2)3—	—C(═O)—NH—	K370	J139	T170
2352	—(CH2)3—	—C(═O)—NH—	K427	J012	T148
2353	—(CH2)3—	—C(═O)—NH—	K428	J045	T170
2354	—(CH2)3—	—C(═O)—NH—	K429	J012	T148
2355	—(CH2)3—	—C(═O)—NH—	K430	J045	T170
2356	—(CH2)3—	—C(═O)—	K240	J012	T148
2357	—(CH2)3—	—C(═O)—	K240	J012	T170
2358	—(CH2)3—	—C(═O)—O—	K001	J002	T148
2359	—(CH2)3—	—C(═O)—O—	K001	J007	T170
2360	—(CH2)3—	—C(═O)—O—	K001	J012	T148
2361	—(CH2)3—	—C(═O)—O—	K002	J044	T170
2362	—(CH2)3—	—C(═O)—O—	K197	J002	T148
2363	—(CH2)3—	—C(═O)—O—	K197	J012	T148
2364	—(CH2)3—	—C(═O)—O—	K197	J012	T170
2365	—(CH2)3—	—C(═O)—O—	K197	J045	T170
2366	—(CH2)3—	—NH—	K185	J007	T148
2367	—(CH2)3—	—NH—	K185	J044	T170
2368	—(CH2)3—	—NH—C(═O)—	K005	J007	T148
2369	—(CH2)3—	—NH—C(═O)—	K005	J044	T170
2370	—(CH2)3—	—NH—C(═O)—	K007	J012	T148
2371	—(CH2)3—	—NH—C(═O)—	K007	J045	T170
2372	—(CH2)3—	—NH—C(═O)—	K008	J012	T148
2373	—(CH2)3—	—NH—C(═O)—	K008	J045	T170
2374	—(CH2)3—	—NH—C(═O)—	K009	J007	T148
2375	—(CH2)3—	—NH—C(═O)—	K009	J044	T170
2376	—(CH2)3—	—NH—C(═O)—	K011	J007	T148
2377	—(CH2)3—	—NH—C(═O)—	K011	J044	T170
2378	—(CH2)3—	—NH—C(═O)—	K013	J007	T148
2379	—(CH2)3—	—NH—C(═O)—	K013	J044	T170
2380	—(CH2)3—	—NH—C(═O)—	K051	J012	T148
2381	—(CH2)3—	—NH—C(═O)—	K051	J045	T170
2382	—(CH2)3—	—NH—C(═O)—	K200	J012	T148
2383	—(CH2)3—	—NH—C(═O)—	K200	J045	T170
2384	—(CH2)3—	—NH—C(═O)—	K204	J007	T148
2385	—(CH2)3—	—NH—C(═O)—	K204	J044	T170
2386	—(CH2)3—	—NH—C(═O)—	K208	J012	T148
2387	—(CH2)3—	—NH—C(═O)—	K208	J045	T170
2388	—(CH2)3—	—NH—C(═O)—	K212	J012	T148
2389	—(CH2)3—	—NH—C(═O)—	K212	J045	T170
2390	—(CH2)3—	—NH—C(═O)—	K262	J012	T148
2391	—(CH2)3—	—NH—C(═O)—	K262	J045	T170
2392	—(CH2)3—	—NH—C(═O)—	K263	J007	T148
2393	—(CH2)3—	—NH—C(═O)—	K263	J044	T170
2394	—(CH2)3—	—NH—C(═O)—	K266	J007	T148
2395	—(CH2)3—	—NH—C(═O)—	K266	J044	T170
2396	—(CH2)3—	—NH—C(═O)—	K272	J012	T148
2397	—(CH2)3—	—NH—C(═O)—	K272	J045	T170
2398	—(CH2)3—	—NH—C(═O)—	K293	J007	T148
2399	—(CH2)3—	—NH—C(═O)—	K293	J044	T170
2400	—(CH2)3—	—NH—C(═O)—NH—	K033	J012	T148
2401	—(CH2)3—	—NH—C(═O)—NH—	K033	J045	T170
2402	—(CH2)3—	—NH—C(═O)—NH—	K333	J007	T148
2403	—(CH2)3—	—NH—C(═O)—NH—	K333	J044	T170
2404	—(CH2)3—	—NH—C(═O)—NH—	K336	J012	T148
2405	—(CH2)3—	—NH—C(═O)—NH—	K336	J045	T170
2406	Single bond	Single bond	K001	J002	T170
2407	Single bond	Single bond	K001	J007	T148
2408	Single bond	Single bond	K001	J007	T170
2409	Single bond	Single bond	K001	J012	T148
2410	Single bond	Single bond	K001	J012	T170
2411	Single bond	Single bond	K001	J029	T148
2412	Single bond	Single bond	K001	J029	T170
2413	Single bond	Single bond	K001	J037	T148
2414	Single bond	Single bond	K001	J037	T170
2415	Single bond	Single bond	K001	J043	T148
2416	Single bond	Single bond	K001	J043	T170
2417	Single bond	Single bond	K001	J044	T148
2418	Single bond	Single bond	K001	J044	T170
2419	Single bond	Single bond	K001	J045	T148
2420	Single bond	Single bond	K001	J045	T170
2421	Single bond	Single bond	K001	J138	T148
2422	Single bond	Single bond	K001	J138	T170
2423	Single bond	Single bond	K001	J144	T148
2424	Single bond	Single bond	K001	J144	T170
2425	Single bond	Single bond	K002	J012	T148
2426	Single bond	Single bond	K002	J012	T170
2427	Single bond	Single bond	K002	J044	T148
2428	Single bond	Single bond	K002	J044	T170
2429	Single bond	Single bond	K002	J045	T170
2430	Single bond	Single bond	K002	J139	T148
2431	Single bond	Single bond	K002	J139	T170
2432	Single bond	Single bond	K197	J002	T148
2433	Single bond	Single bond	K197	J002	T170
2434	Single bond	Single bond	K197	J007	T148
2435	Single bond	Single bond	K197	J007	T170
2436	Single bond	Single bond	K197	J008	T148
2437	Single bond	Single bond	K197	J008	T170
2438	Single bond	Single bond	K197	J010	T148
2439	Single bond	Single bond	K197	J010	T170
2440	Single bond	Single bond	K197	J012	T170
2441	Single bond	Single bond	K197	J013	T148
2442	Single bond	Single bond	K197	J013	T170
2443	Single bond	Single bond	K197	J014	T148
2444	Single bond	Single bond	K197	J014	T170
2445	Single bond	Single bond	K197	J018	T148
2446	Single bond	Single bond	K197	J022	T148
2447	Single bond	Single bond	K197	J022	T170
2448	Single bond	Single bond	K197	J026	T148
2449	Single bond	Single bond	K197	J026	T170
2450	Single bond	Single bond	K197	J027	T148
2451	Single bond	Single bond	K197	J027	T170
2452	Single bond	Single bond	K197	J028	T148
2453	Single bond	Single bond	K197	J028	T170
2454	Single bond	Single bond	K197	J029	T148
2455	Single bond	Single bond	K197	J029	T169
2456	Single bond	Single bond	K197	J029	T170
2457	Single bond	Single bond	K197	J030	T148
2458	Single bond	Single bond	K197	J030	T170
2459	Single bond	Single bond	K197	J031	T148
2460	Single bond	Single bond	K197	J031	T170
2461	Single bond	Single bond	K197	J032	T148
2462	Single bond	Single bond	K197	J032	T170
2463	Single bond	Single bond	K197	J034	T148
2464	Single bond	Single bond	K197	J034	T170
2465	Single bond	Single bond	K197	J036	T148
2466	Single bond	Single bond	K197	J036	T170
2467	Single bond	Single bond	K197	J037	T148
2468	Single bond	Single bond	K197	J037	T170
2469	Single bond	Single bond	K197	J039	T148
2470	Single bond	Single bond	K197	J039	T170
2471	Single bond	Single bond	K197	J043	T148
2472	Single bond	Single bond	K197	J043	T170
2473	Single bond	Single bond	K197	J044	T148
2474	Single bond	Single bond	K197	J044	T170
2475	Single bond	Single bond	K197	J045	T148
2476	Single bond	Single bond	K197	J045	T170
2477	Single bond	Single bond	K197	J090	T148
2478	Single bond	Single bond	K197	J090	T170
2479	Single bond	Single bond	K197	J092	T148
2480	Single bond	Single bond	K197	J092	T170
2481	Single bond	Single bond	K197	J144	T148
2482	Single bond	Single bond	K197	J121	T148
2483	Single bond	Single bond	K197	J121	T170
2484	Single bond	Single bond	K197	J137	T148
2485	Single bond	Single bond	K197	J137	T170
2486	Single bond	Single bond	K197	J138	T148
2487	Single bond	Single bond	K197	J138	T170
2488	Single bond	Single bond	K197	J139	T148
2489	Single bond	Single bond	K197	J139	T170
2490	Single bond	Single bond	K197	J141	T148
2491	Single bond	Single bond	K197	J141	T170
2492	Single bond	Single bond	K197	J142	T148
2493	Single bond	Single bond	K197	J142	T169
2494	Single bond	Single bond	K197	J142	T170
2495	Single bond	Single bond	K197	J143	T148
2496	Single bond	Single bond	K197	J143	T170
2497	Single bond	Single bond	K197	J107	T148
2498	Single bond	Single bond	K197	J144	T170
2499	Single bond	Single bond	K223	J001	T164
2500	Single bond	Single bond	K223	J138	T148
2501	—(CH2)3—	—C(═O)—O—	K002	J001	T001
2502	—(CH2)3—	—C(═O)—O—	K002	J001	T005
2503	—(CH2)3—	—C(═O)—O—	K197	J001	T148
2504	—(CH2)3—	—C(═O)—O—	K002	J002	T148
2505	—(CH2)3—	—C(═O)—O—	K197	J002	T170
2506	—(CH2)3—	—C(═O)—NH—	K346	J002	T170
2507	—(CH2)3—	—C(═O)—O—	K002	J012	T001
2508	—(CH2)3—	—C(═O)—O—	K002	J012	T005
2509	—(CH2)3—	—C(═O)—O—	K002	J012	T148
2510	—(CH2)3—	—C(═O)—O—	K002	J012	T170
2511	—(CH2)2—	—NH—C(═O)—	K005	J012	T004
2512	—(CH2)3—	—C(═O)—O—	K002	J001	T148
2513	—(CH2)2—	—NH—C(═O)—O—	K005	J045	T181
2514	—(CH2)2—	—NH—C(═O)—	K338	J012	T148

Also, among compounds described in Table 1, compounds of the following numbers are more preferred.

Compound numbers 19, 20, 22, 27, 29, 30, 34, 36, 37, 38, 39, 40, 41, 42, 43, 44, 46, 47, 48, 49, 50, 51, 52, 53, 54, 56, 57, 58, 59, 60, 61, 62, 63, 64, 66, 67, 68, 69, 70, 71, 72, 73, 74, 76, 77, 78, 79, 81, 84, 85, 86, 87, 88, 90, 91, 92, 93, 94, 95, 96, 97, 98, 100, 101, 102, 103, 104, 105, 106, 107, 108, 110, 111, 112, 113, 114, 115, 116, 117, 118, 120, 121, 122, 123, 124, 125, 126, 127, 128, 130, 131, 132, 133, 134, 135, 136, 137, 138, 140, 141, 142, 143, 144, 145, 146, 147, 148, 150, 151, 152, 153, 154, 155, 156, 157, 158, 160, 161, 162, 163, 164, 165, 166, 167, 168, 170, 171, 172, 173, 174, 175, 176, 177, 178, 180, 181, 182, 183, 184, 185, 186, 187, 188, 190, 191, 192, 193, 194, 195, 196, 197, 198, 200, 201, 202, 203, 206, 210, 211, 213, 214, 217, 219, 221, 223, 225, 226, 227, 228, 229, 230, 231, 232, 237, 240, 241, 242, 243, 244, 245, 250, 253, 254, 255, 257, 258, 260, 261, 262, 263, 265, 266, 267, 268, 269, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 320, 321, 327, 328, 330, 331, 332, 333, 334, 335, 340, 342, 343, 348, 349, 350, 351, 352, 353, 359, 361, 362, 363, 364, 365, 366, 368, 369, 371, 373, 379, 381, 382, 383, 384, 385, 386, 387, 392, 393, 395, 397, 398, 399, 400, 401, 407, 409, 410, 411, 412, 413, 415, 416, 417, 418, 419, 420, 421, 422, 423, 426, 427, 429, 430, 431, 432, 433, 434, 437, 438, 439, 445, 447, 448, 449, 451, 453, 454, 455, 456, 457, 463, 465, 466, 467, 468, 469, 471, 472, 473, 474, 475, 476, 477, 478, 479, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 497, 498, 499, 501, 502, 503, 504, 509, 511, 512, 513, 515, 517, 518, 519, 520, 521, 527, 529, 530, 531, 532, 533, 534, 535, 536, 537, 539, 540, 541, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 555, 556, 557, 563, 565, 566, 567, 569, 571, 572, 573, 574, 575, 581, 583, 584, 585, 586, 587, 589, 590, 591, 593, 594, 595, 596, 597, 599, 600, 601, 602, 605, 606, 607, 608, 610, 611, 612, 613, 615, 616, 617, 618, 620, 621, 623, 624, 625, 626, 627, 628, 629, 630, 631, 634, 635, 638, 639, 641, 642, 643, 644, 645, 646, 647, 648, 651, 652, 653, 655, 656, 657, 658, 659, 660, 661, 662, 663, 664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 675, 676, 677, 678, 679, 681, 682, 683, 684, 685, 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696, 697, 700, 701, 702, 704, 705, 706, 707, 709, 710, 711, 712, 713, 715, 716, 717, 718, 719, 721, 722, 723, 724, 725, 726, 727, 728, 729, 730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 740, 741, 743, 744, 745, 747, 748, 749, 750, 751, 752, 753, 754, 755, 756, 757, 758, 759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 769, 770, 771, 773, 776, 777, 778, 779, 780, 781, 782, 783, 784, 785, 786, 787, 788, 789, 790, 791, 792, 793, 794, 795, 796, 801, 802, 803, 804, 805, 806, 807, 808, 809, 810, 811, 812, 852, 853, 874, 892, 893, 915, 917, 918, 919, 921, 939, 946, 998, 1000, 1001, 1002, 1007, 1008, 1014, 1015, 1054, 1055, 1056, 1059, 1061, 1063, 1065, 1067, 1069, 1071, 1073, 1075, 1076, 1077, 1078, 1079, 1080, 1081, 1083, 1085, 1089, 1090, 1091, 1092, 1093, 1095, 1096, 1097, 1098, 1099, 1103, 1104, 1106, 1110, 1112, 1113, 1115, 1117, 1118, 1120, 1121, 1127, 1129, 1130, 1131, 1132, 1134, 1137, 1140, 1143, 1146, 1151, 1152, 1153, 1155, 1156, 1158, 1159, 1161, 1165, 1166, 1167, 1168, 1170, 1178, 1181, 1182, 1183, 1184, 1185, 1186, 1187, 1188, 1189, 1190, 1191, 1192, 1193, 1194, 1195, 1196, 1197, 1198, 1199, 1200, 1201, 1202, 1203, 1204, 1205, 1206, 1207, 1208, 1209, 1210, 1211, 1212, 1213, 1214, 1215, 1216, 1217, 1218, 1219, 1220, 1221, 1222, 1223, 1224, 1225, 1226, 1227, 1228, 1229, 1230, 1231, 1232, 1233, 1234, 1235, 1236, 1237, 1238, 1239, 1240, 1241, 1242, 1243, 1244, 1245, 1246, 1247, 1248, 1249, 1250, 1251, 1252, 1253, 1254, 1255, 1256, 1257, 1258, 1259, 1260, 1261, 1262, 1263, 1264, 1265, 1266, 1268, 1269, 1270, 1271, 1272, 1273, 1274, 1275, 1276, 1277, 1278, 1279, 1280, 1281, 1282, 1283, 1284, 1285, 1286, 1287, 1288, 1289, 1291, 1292, 1293, 1294, 1295, 1296, 1297, 1298, 1299, 1300, 1301, 1302, 1303, 1304, 1305, 1306, 1307, 1308, 1309, 1310, 1311, 1312, 1313, 1314, 1315, 1316, 1317, 1318, 1319, 1320, 1321, 1322, 1323, 1324, 1325, 1326, 1327, 1328, 1329, 1330, 1331, 1332, 1333, 1334, 1335, 1336, 1337, 1338, 1339, 1340, 1341, 1342, 1343, 1344, 1345, 1346, 1347, 1348, 1349, 1350, 1351, 1352, 1353, 1354, 1355, 1356, 1357, 1358, 1359, 1360, 1361, 1362, 1363, 1364, 1365, 1366, 1367, 1368, 1369, 1370, 1371, 1372, 1373, 1374, 1375, 1376, 1377, 1378, 1379, 1380, 1381, 1382, 1383, 1384, 1385, 1386, 1387, 1388, 1389, 1390, 1391, 1392, 1393, 1394, 1395, 1396, 1397, 1398, 1399, 1400, 1401, 1402, 1403, 1404, 1405, 1406, 1407, 1408, 1409, 1410, 1411, 1412, 1413, 1414, 1415, 1416, 1417, 1418, 1419, 1420, 1421, 1422, 1423, 1424, 1425, 1426, 1427, 1428, 1429, 1430, 1431, 1432, 1433, 1434, 1435, 1436, 1437, 1438, 1439, 1440, 1441, 1442, 1443, 1444, 1445, 1446, 1447, 1448, 1449, 1450, 1451, 1452, 1453, 1454, 1455, 1456, 1457, 1458, 1459, 1460, 1461, 1462, 1463, 1464, 1465, 1466, 1467, 1468, 1469, 1470, 1471, 1472, 1473, 1474, 1475, 1476, 1477, 1478, 1479, 1480, 1481, 1482, 1483, 1484, 1485, 1486, 1487, 1488, 1489, 1490, 1491, 1492, 1493, 1494, 1495, 1496, 1497, 1498, 1499, 1500, 1501, 1502, 1503, 1504, 1505, 1506, 1507, 1508, 1509, 1510, 1511, 1512, 1513, 1514, 1515, 1516, 1517, 1518, 1519, 1520, 1521, 1522, 1523, 1524, 1525, 1526, 1527, 1528, 1529, 1530, 1531, 1532, 1533, 1534, 1535, 1536, 1537, 1538, 1539, 1540, 1541, 1542, 1543, 1544, 1545, 1546, 1547, 1548, 1549, 1550, 1551, 1552, 1553, 1554, 1555, 1556, 1557, 1558, 1559, 1560, 1561, 1562, 1563, 1564, 1565, 1566, 1567, 1568, 1569, 1570, 1571, 1572, 1573, 1574, 1575, 1576, 1577, 1578, 1579, 1580, 1581, 1582, 1583, 1584, 1585, 1586, 1587, 1588, 1589, 1590, 1591, 1592, 1593, 1594, 1595, 1596, 1597, 1598, 1599, 1600, 1601, 1602, 1603, 1604, 1605, 1606, 1607, 1608, 1609, 1610, 1611, 1612, 1613, 1614, 1615, 1616, 1617, 1618, 1619, 1620, 1621, 1622, 1623, 1624, 1625, 1626, 1627, 1628, 1629, 1630, 1631, 1632, 1633, 1634, 1635, 1636, 1637, 1638, 1639, 1640, 1641, 1642, 1643, 1644, 1645, 1646, 1647, 1648, 1649, 1650, 1651, 1652, 1653, 1654, 1655, 1656, 1657, 1658, 1659, 1660, 1661, 1662, 1663, 1664, 1665, 1666, 1667, 1668, 1669, 1670, 1671, 1672, 1673, 1674, 1675, 1676, 1677, 1678, 1679, 1680, 1681, 1682, 1683, 1684, 1685, 1686, 1687, 1688, 1689, 1690, 1691, 1692, 1693, 1694, 1695, 1696, 1697, 1698, 1700, 1701, 1702, 1703, 1704, 1705, 1706, 1707, 1708, 1709, 1710, 1711, 1712, 1713, 1714, 1715, 1716, 1717, 1718, 1719, 1720, 1721, 1722, 1723, 1724, 1725, 1726, 1727, 1728, 1729, 1730, 1731, 1732, 1733, 1734, 1735, 1736, 1737, 1738, 1739, 1740, 1741, 1742, 1743, 1744, 1745, 1746, 1747, 1748, 1749, 1750, 1751, 1752, 1753, 1754, 1755, 1756, 1757, 1758, 1759, 1760, 1761, 1762, 1763, 1764, 1765, 1766, 1767, 1768, 1769, 1770, 1771, 1772, 1773, 1774, 1775, 1776, 1777, 1778, 1779, 1780, 1781, 1782, 1783, 1784, 1785, 1786, 1787, 1788, 1789, 1790, 1791, 1792, 1793, 1794, 1795, 1796, 1797, 1798, 1799, 1800, 1801, 1802, 1803, 1804, 1805, 1806, 1807, 1808, 1809, 1810, 1811, 1812, 1813, 1814, 1815, 1816, 1817, 1818, 1819, 1820, 1821, 1822, 1823, 1824, 1825, 1826, 1827, 1829, 1830, 1831, 1832, 1833, 1834, 1835, 1836, 1837, 1838, 1839, 1840, 1841, 1842, 1843, 1844, 1845, 1846, 1847, 1848, 1849, 1850, 1851, 1852, 1853, 1854, 1855, 1856, 1857, 1858, 1859, 1860, 1861, 1862, 1863, 1864, 1865, 1866, 1867, 1868, 1869, 1870, 1871, 1872, 1873, 1874, 1875, 1876, 1877, 1878, 1879, 1880, 1881, 1882, 1883, 1884, 1885, 1886, 1887, 1888, 1889, 1890, 1891, 1892, 1893, 1894, 1895, 1896, 1897, 1898, 1899, 1900, 1901, 1902, 1903, 1904, 1905, 1906, 1907, 1908, 1909, 1910, 1911, 1912, 1913, 1914, 1915, 1916, 1917, 1918, 1919, 1920, 1921, 1922, 1923, 1924, 1925, 1926, 1927, 1928, 1929, 1930, 1931, 1932, 1933, 1934, 1935, 1936, 1937, 1938, 1939, 1940, 1941, 1942, 1943, 1944, 1945, 1946, 1947, 1948, 1949, 1950, 1951, 1952, 1953, 1954, 1955, 1956, 1957, 1958, 1959, 1960, 1961, 1962, 1963, 1964, 1965, 1966, 1967, 1968, 1969, 1970, 1971, 1972, 1973, 1974, 1975, 1976, 1977, 1978, 1979, 1980, 1981, 1982, 1983, 1984, 1985, 1986, 1987, 1988, 1989, 1990, 1991, 1992, 1993, 1994, 1995, 1996, 1997, 1998, 1999, 2000, 2001, 2002, 2003, 2004, 2005, 2006, 2007, 2008, 2010, 2011, 2012, 2013, 2014, 2015, 2016, 2017, 2018, 2019, 2020, 2021, 2022, 2023, 2024, 2025, 2026, 2027, 2028, 2029, 2030, 2031, 2032, 2033, 2034, 2035, 2036, 2037, 2038, 2039, 2040, 2041, 2042, 2043, 2044, 2045, 2046, 2047, 2048, 2049, 2050, 2051, 2052, 2053, 2054, 2055, 2056, 2057, 2058, 2059, 2060, 2061, 2062, 2063, 2064, 2065, 2066, 2067, 2068, 2069, 2070, 2071, 2072, 2073, 2074, 2075, 2076, 2077, 2078, 2079, 2080, 2081, 2082, 2083, 2084, 2085, 2086, 2087, 2088, 2089, 2090, 2091, 2092, 2093, 2094, 2095, 2096, 2097, 2098, 2099, 2100, 2101, 2102, 2103, 2104, 2105, 2106, 2107, 2108, 2109, 2111, 2112, 2113, 2114, 2115, 2116, 2117, 2118, 2119, 2121, 2122, 2123, 2124, 2125, 2128, 2129, 2130, 2131, 2132, 2133, 2134, 2135, 2136, 2137, 2138, 2139, 2140, 2143, 2144, 2145, 2146, 2147, 2148, 2149, 2150, 2151, 2152, 2153, 2154, 2155, 2156, 2157, 2158, 2159, 2160, 2161, 2162, 2163, 2164, 2166, 2167, 2168, 2169, 2170, 2171, 2172, 2173, 2174, 2175, 2176, 2177, 2178, 2179, 2180, 2181, 2182, 2183, 2184, 2185, 2186, 2187, 2188, 2189, 2190, 2191, 2192, 2193, 2194, 2195, 2196, 2197, 2198, 2199, 2200, 2201, 2202, 2203, 2204, 2205, 2206, 2207, 2208, 2209, 2210, 2211, 2212, 2213, 2214, 2215, 2216, 2217, 2218, 2219, 2220, 2221, 2222, 2223, 2224, 2225, 2226, 2227, 2228, 2229, 2230, 2231, 2232, 2233, 2234, 2235, 2236, 2237, 2238, 2239, 2240, 2241, 2242, 2243, 2244, 2245, 2246, 2247, 2248, 2249, 2250, 2251, 2252, 2253, 2254, 2255, 2256, 2257, 2258, 2259, 2260, 2261, 2262, 2263, 2264, 2265, 2266, 2267, 2268, 2269, 2270, 2271, 2272, 2273, 2274, 2275, 2276, 2277, 2278, 2279, 2280, 2281, 2282, 2283, 2284, 2285, 2286, 2288, 2289, 2290, 2291, 2292, 2293, 2294, 2295, 2296, 2297, 2298, 2299, 2300, 2302, 2303, 2304, 2305, 2306, 2307, 2308, 2309, 2310, 2311, 2312, 2313, 2314, 2315, 2316, 2317, 2318, 2319, 2320, 2321, 2322, 2323, 2324, 2325, 2326, 2327, 2328, 2329, 2330, 2331, 2332, 2333, 2334, 2335, 2336, 2337, 2338, 2339, 2340, 2341, 2342, 2343, 2344, 2345, 2346, 2347, 2348, 2349, 2350, 2351, 2352, 2353, 2354, 2355, 2356, 2357, 2358, 2359, 2360, 2361, 2363, 2364, 2365, 2366, 2367, 2368, 2369, 2370, 2371, 2372, 2373, 2374, 2375, 2376, 2377, 2378, 2379, 2380, 2381, 2382, 2383, 2384, 2385, 2386, 2387, 2388, 2389, 2390, 2391, 2392, 2393, 2394, 2395, 2396, 2397, 2398, 2399, 2400, 2401, 2402, 2403, 2404, 2405, 2406, 2407, 2408, 2409, 2410, 2411, 2412, 2413, 2414, 2415, 2416, 2417, 2418, 2419, 2420, 2421, 2422, 2423, 2424, 2425, 2426, 2427, 2428, 2429, 2430, 2431, 2433, 2434, 2435, 2436, 2437, 2438, 2439, 2440, 2441, 2442, 2443, 2444, 2445, 2446, 2447, 2448, 2449, 2450, 2451, 2452, 2453, 2454, 2455, 2456, 2457, 2458, 2459, 2460, 2461, 2462, 2463, 2464, 2465, 2466, 2467, 2468, 2469, 2470, 2471, 2472, 2473, 2474, 2475, 2476, 2477, 2478, 2479, 2480, 2481, 2482, 2483, 2484, 2485, 2486, 2487, 2488, 2489, 2490, 2491, 2492, 2493, 2494, 2495, 2496, 2497, 2498, 2505, 2506, 2509, 2510, 2514.

Preferred combinations of A¹, A², G¹, A³, A⁴ and G² in the formula (I) were explained above. As another method of arrangement, they can be summarized also as the following combinations 1) through 41). Not only do these combinations indicate preferred relationships among A¹, A², G¹, A³, A⁴ and G², but also the partial structures per se comprised of these as a whole are preferred substituents in the pyrrolopyrimidinone derivatives of the present invention.

1) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the form of A¹-NH—C(═O)-G¹, and G¹ is a phenylene group, the phenylene group as G¹ is preferably substituted with one or more substituents selected from those exemplified for the preferred substituents of the substituted aromatic hydrocarbon group having 6 to 14 carbon atoms of G¹.

2) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the form of A¹-NH—C(═O)-G¹, G¹ is a phenylene group, and the phenylene group as G¹ is not substituted, it is preferable that A³-A⁴-G² as a whole is a group other than a hydrogen atom.

3) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the form of A¹-NH—C(═O)-G¹, G¹ is preferably a divalent group derived from a monocyclic or bicyclic C₃-C₉ aromatic heterocyclic compound having 1 to 3, preferably 1 or 2, atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring.

4) In the formula (I), when A¹ is —(CH₂)₂— and A¹-A²-G¹ links in the form of A¹-NH—C(═O)-G¹, G¹ is preferably a divalent group derived from a monocyclic or bicyclic C₂-C₉ aromatic heterocyclic compound having 1 to 3, preferably 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring. However, the divalent group derived from the aromatic heterocyclic compound as G¹ is more preferably substituted with one or more substituents selected from the group consisting of substituents defined as preferred examples for the heterocyclic compound having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring.

5) In the formula (I), when A¹ is —(CH₂)₂— and A¹-A²-G¹ links in the form of A¹-NH—C(═O)-G¹, G¹ is preferably a divalent group derived from a monocyclic or bicyclic C₂-C₉ aromatic heterocyclic compound having 1 to 3, preferably 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring. However, when the divalent group derived from the aromatic heterocyclic compound as G¹ is not substituted, it is more preferable that A³-A⁴-G² as a whole is a group other than a hydrogen atom.

6) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the form of A¹-NH—C(═O)-G¹, and G¹ represents a single bond, it is more preferable that A³-A⁴-G² as a whole is a acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms or a cycloalkylalkyl group consisting of a acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms and an alicyclic hydrocarbon group having 3 to 8 carbon atoms.

7) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the form of A¹-NH—C(═O)-G¹, and G¹ represents a single bond, A³-A⁴-G² is preferably a acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms or a cycloalkylalkyl group consisting of a acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms and an alicyclic hydrocarbon group having 3 to 8 carbon atoms as a whole, but a acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms as A³-A⁴-G² is more preferably substituted with one or more substituents selected from those exemplified for the preferred substituents of the substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms of A³. Also, in a cycloalkylalkyl group consisting of a acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms and an alicyclic hydrocarbon group having 3 to 8 carbon atoms as A³-A⁴-G², a acyclic aliphatic hydrocarbon group portion having 1 to 6 carbon atoms is further preferably substituted with one or more substituents selected from those exemplified for the preferred substituents of the substituted aliphatic hydrocarbon group having 1 to 10 carbon atoms of A³, or an alicyclic hydrocarbon group portion having 3 to 8 carbon atoms is further preferably substituted with one or more substituents selected from those exemplified for the preferred substituents of the substituted alicyclic hydrocarbon group having 3 to 10 carbon atoms of G² (including a case where both are substituted).

8) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the form of A¹-NH—C(═O)-G¹, and G¹ represents a single bond, A³-A⁴-G² is preferably an aralkyl group consisting of a acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms and an aromatic hydrocarbon group having 6 to 10 carbon atoms as a whole.

9) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the form of A¹-NH—C(═O)-G¹, and G¹ represents a single bond, A³-A⁴-G² is preferably an aralkyl group consisting of a acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms and an aromatic hydrocarbon group having 6 to 10 carbon atoms as a whole, but in an aralkyl group as A³-A⁴-G², a acyclic aliphatic hydrocarbon group portion having 1 to 6 carbon atoms is further preferably substituted with one or more substituents selected from those exemplified for the preferred substituents of the substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms of A³, or an aromatic hydrocarbon group portion having 6 to 10 carbon atoms is further preferably substituted with one or more substituents selected from those exemplified for the preferred substituents of the substituted aromatic hydrocarbon group having 6 to 14 carbon atoms of G² (including a case where both are substituted).

10) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the form of A¹-NH—C(═O)-G¹, and G¹ represents a single bond, A³-A⁴-G² is preferably a heterocyclic substituted alkyl group consisting of a acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms and a heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring as a whole.

11) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the form of A¹-NH—C(═O)-G¹, and G¹ represents a single bond, A³-A⁴-G² is preferably a heterocyclic substituted alkyl group consisting of a acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms and a heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring as a whole. However, in the heterocyclic substituted alkyl group as A³-A⁴-G², a acyclic aliphatic hydrocarbon group portion having 1 to 6 carbon atoms is further preferably substituted with one or more substituents selected from those exemplified for the preferred substituents of the substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms of A³, or a heterocyclic portion is further preferably substituted with one or more substituents selected from those exemplified for the preferred substituents of the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, of G² (including a case where both are substituted).

12) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the form of A¹-NH—C(═O)-G¹, and G¹ is a phenylene group, the phenylene group as G¹ is preferably substituted with one or more substituents selected from those exemplified for the preferred substituents of the substituted aromatic hydrocarbon group having 6 to 14 carbon atoms of G¹.

13) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the form of A¹-NH—C(═O)—NH-G¹, G¹ is a phenylene group, and the phenylene group as G¹ is not substituted, it is preferable that A³-A⁴-G² as a whole is a group other than a hydrogen atom.

14) In the formula (I), when A¹ is —(CH)₂— and A¹-A²-G¹ links in the form of A¹-NH—C(═O)—NH-G¹, G¹ is preferably a divalent group derived from a monocyclic or bicyclic C₃-C₉ aromatic heterocyclic compound having 1 to 3, preferably 1 or 2, atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring.

15) In the formula (I), when A¹ is —(CH₂)₂— and A¹-A²-G¹ links in the form of A¹-NH—C(═O)—NH-G¹, G¹ is preferably a divalent group derived from a monocyclic or bicyclic C₂-C₉ aromatic heterocyclic compound having 1 to 3, preferably 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring. However, the divalent group derived from the aromatic heterocyclic compound as G¹ is more preferably substituted with one or more substituents selected from the group consisting of substituents defined as preferred examples for the heterocyclic compound having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring.

16) In the formula (I), when A¹ is —(CH₂)₂— and A¹-A²-G¹ links in the form of A¹-NH—C(═O)—NH-G¹, G¹ is preferably a divalent group derived from a monocyclic or bicyclic C₂-C₉ aromatic heterocyclic compound having 1 to 3, preferably 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring. However, when the divalent group derived from the aromatic heterocyclic compound as G¹ is not substituted, it is more preferable that A³-A⁴-G² as a whole is a group other than a hydrogen atom.

17) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the form of A¹-NH—C(═O)—NH-G¹, and G¹ represents a single bond, it is more preferable that A³-A⁴-G² as a whole is a cycloalkylalkyl group consisting of a acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms and an alicyclic hydrocarbon group having 3 to 8 carbon atoms.

18) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the form of A¹-NH—C(═O)—NH-G¹, and G¹ represents a single bond, it is more preferable that A³-A⁴-G² as a whole is a cycloalkylalkyl group consisting of a acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms and an alicyclic hydrocarbon group having 3 to 8 carbon atoms. However, in the cycloalkylalkyl group as A³-A⁴-G², a acyclic aliphatic hydrocarbon group portion having 1 to 6 carbon atoms is more preferably substituted with one or more substituents selected from those exemplified for the preferred substituents of the substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms of A³, or an alicyclic hydrocarbon group portion having 3 to 8 carbon atoms is further preferably substituted with one or more substituents selected from those exemplified for the preferred substituents of the substituted alicyclic hydrocarbon group having 3 to 10 carbon atoms of G² (including a case where both are substituted).

19) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the form of A¹-NH—C(═O)—NH-G¹, and G¹ represents a single bond, it is more preferable that A³-A⁴-G² as a whole is an aralkyl group consisting of a acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms and an aromatic hydrocarbon group having 6 to 10 carbon atoms.

20) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the form of A¹-NH—C(═O)—NH-G¹, and G¹ represents a single bond, it is more preferable that A³-A⁴-G² as a whole is an aralkyl group consisting of a acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms and an aromatic hydrocarbon group having 6 to 14 carbon atoms. However, in the ararkyl group as A³-A⁴-G², a acyclic aliphatic hydrocarbon group portion having 1 to 6 carbon atoms is more preferably substituted with one or more substituents selected from those exemplified for the preferred substituents of the substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms of A³, or an aromatic hydrocarbon group portion having 6 to 10 carbon atoms is further preferably substituted with one or more substituents selected from those exemplified for the preferred substituents of the substituted aromatic hydrocarbon group having 6 to 14 carbon atoms of G² (including a case where both are substituted).

21) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the form of A¹-NH—C(═O)—NH-G¹, and G¹ represents a single bond, it is preferable that A³-A⁴-G² as a whole is a heterocyclic substituted alkyl group consisting of a acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms and a heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring.

22) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the form of A¹-NH—C(═O)—NH-G¹, and G¹ represents a single bond, it is preferable that A³-A⁴-G² as a whole is a heterocyclic substituted alkyl group consisting of a acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms and a heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring. However, in the heterocyclic substituted alkyl group as A³-A⁴-G², a acyclic aliphatic hydrocarbon group portion having 1 to 6 carbon atoms is further preferably substituted with one or more substituents selected from those exemplified for the preferred substituents of the substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms of A³, or a heterocyclic group portion is further preferably substituted with one or more substituents selected from those exemplified for the preferred substituents of the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, of G² (including a case where both are substituted).

23) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the form of A¹-NH-G¹, and G¹ is a phenylene group, the phenylene group as G¹ is preferably substituted with one or more substituents selected from those exemplified for the preferred substituents of the substituted aromatic hydrocarbon group having 6 to 14 carbon atoms of G¹.

24) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the form of A¹-NH-G¹, G¹ is a phenylene group, and the phenylene group as G¹ is not substituted, it is preferable that A³-A⁴-G² as a whole is a group other than a hydrogen atom.

25) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the form of A¹-NH-G¹, and G¹ is a divalent group derived from a monocyclic or bicyclic C₂-C₉ aromatic heterocyclic compound having 1 to 3 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, the aromatic heterocyclic group is preferably substituted with one or more substituents selected from the group consisting of substituents defined as preferred examples for the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring.

26) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the form of A¹-NH-G¹, G¹ is a divalent group derived from a monocyclic or bicyclic C₂-C₉ aromatic heterocyclic compound having 1 to 3 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, and the aromatic heterocyclic compound is not substituted, it is more preferable that A³-A⁴-G² as a whole is a group other than a hydrogen atom.

27) In the formula (I), when A¹ is —(CH₂)₂— and A¹-A²-G¹ links in the form of A¹-C(═O)-G¹, G¹ is preferably a divalent group derived from a monocyclic C₂-C₉ heterocyclic compound having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, such as pyrrolidine, piperidine, morpholine, thiomorpholine, homopiperidine, homopiperazine, 1,2,3,6-tetrahydropyridine or piperazine, and G¹ is bonded with A¹-C(═O)— through a nitrogen atom.

28) In the formula (I), when A¹ is —(CH₂)₂— and A¹-A²-G¹ links in the form of A¹-C(═O)-G¹, G¹ is a preferably divalent group derived from a monocyclic C₂-C₉ heterocyclic compound having 1 or 2 atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, such as pyrrolidine, piperidine, morpholine, thiomorpholine, homopiperidine, homopiperazine, 1,2,3,6-tetrahydropyridine or piperazine, and G¹ is preferably bonded with A¹-C(═O)— through a nitrogen atom. However, the divalent group derived from the monocyclic C₂-C₉ heterocyclic compound having 1 or 2 atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, in the ring as G¹ is more preferably substituted with one or more substituents selected from the group consisting of substituents defined as proffered examples for the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on the substituted ring of G¹.

29) In the formula (I), when A¹ is —(CH₂)₂— and A¹-A²-G¹ links in the form of A¹-C(═O)-G¹, G¹ is a preferably divalent group derived from a monocyclic C₂-C₉ heterocyclic compound having 1 or 2 atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, such as pyrrolidine, piperidine, morpholine, thiomorpholine, homopiperidine, homopiperazine, 1,2,3,6-tetrahydropyridine or piperazine, and G¹ is preferably bonded with A¹-C(═O)— through a nitrogen atom. However, when the divalent group derived from the monocyclic C₂-C₉ heterocyclic compound having 1 or 2 atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, in the ring as G¹ is not substituted, it is more preferable that A³-A⁴-G² as a whole is a group other than a hydrogen atom.

30) In the formula (I), when A¹ is —(CH₂)₃—, A¹-A²-G¹ links in the form of A¹-C(═O)—NH-G¹, and G¹ is a phenylene group, the phenylene group as G¹ is preferably substituted with one or more substituents selected from those exemplified for the preferred substituents of the substituted aromatic hydrocarbon group having 6 to 14 carbon atoms of G¹.

31) In the formula (I), when A¹ is —(CH₂)₂—, A¹-A²-G¹ links in the form of A¹-C(═O)—NH-G¹, G¹ is a phenylene group, and the phenylene group as G¹ is not substituted, it is preferable that A³-A⁴-G² as a whole is a group other than a hydrogen atom.

32) In the formula (I), when A¹ is —(CH₂)₃— and A¹-A²-G¹ links in the form of A¹-C(═O)—NH-G¹, G¹ is preferably a divalent group derived from a monocyclic or bicyclic C₃-C₉ aromatic heterocyclic compound having 1 to 3, preferably 1 or 2, atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring.

33) In the formula (I), when A¹ is —(CH₂)₃— and A¹-A²-G¹ links in the form of A¹-C(═O)—NH-G¹, G¹ is preferably a divalent group derived from a monocyclic or bicyclic C₂-C₉ aromatic heterocyclic compound having 1 to 3, preferably 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring. However, the divalent group derived from the aromatic heterocyclic compound as G¹ is more preferably substituted with one or more substituents selected from the group consisting of substituents defined as preferred examples for the heterocyclic compound having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring.

34) In the formula (I), when A¹ is —(CH₂)₃— and A¹-A²-G¹ links in the form of A¹-C(═O)—NH-G¹, G¹ is preferably a divalent group derived from a monocyclic or bicyclic C₂-C₉ aromatic heterocyclic compound having 1 to 3, preferably 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring. However, when the divalent group derived from the aromatic heterocyclic compound as G¹ is not substituted, it is more preferable that A³-A⁴-G² as a whole is a group other than a hydrogen atom.

35) In the formula (I), when A¹ is —(CH₂)₃—, A¹-A²-G¹ links in the form of A¹-C(═O)—NH-G¹, and G¹ represents a single bond, it is more preferable that A³-A⁴-G² as a whole is a cycloalkylalkyl group consisting of a acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms and an alicyclic hydrocarbon group having 3 to 8 carbon atoms.

36) In the formula (I), when A¹ is —(CH₂)₃—, A¹-A²-G¹ links in the form of A¹-C(═O)—NH-G¹, and G¹ represents a single bond, it is more preferable that A³-A⁴-G² as a whole is a cycloalkylalkyl group consisting of a acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms and an alicyclic hydrocarbon group having 3 to 8 carbon atoms. However, in the cycloalkylalkyl group as A³-A⁴-G², a acyclic aliphatic hydrocarbon group portion having 1 to 6 carbon atoms is more preferably substituted with one or more substituents selected from those exemplified for the preferred substituents of the substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms of A³, or an alicyclic hydrocarbon group portion having 3 to 8 carbon atoms is further preferably substituted with one or more substituents selected from those exemplified for the preferred substituents of the substituted alicyclic hydrocarbon group having 3 to 10 carbon atoms of G² (including a case where the both are substituted).

37) In the formula (I), when A¹ is —(CH₂)₃—, A¹-A²-G¹ links in the form of A¹-C(═O)—NH-G¹, and G¹ represents a single bond, it is more preferable that A³-A⁴-G² as a whole is an aralkyl group consisting of a acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms and an aromatic hydrocarbon group having 6 to 14 carbon atoms.

38) In the formula (I), when A¹ is —(CH₂)₃—, A¹-A²-G¹ links in the form of A¹-C(═O)—NH-G¹, and G¹ represents a single bond, it is more preferable that A³-A⁴-G² as a whole is an aralkyl group consisting of a acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms and an aromatic hydrocarbon group having 6 to 10 carbon atoms. However, in the aralkyl group as A³-A⁴-G², a acyclic aliphatic hydrocarbon group portion having 1 to 6 carbon atoms is more preferably substituted with one or more substituents selected from those exemplified for the preferred substituents of the substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms of A³, or an aromatic hydrocarbon group portion having 6 to 10 carbon atoms is further preferably substituted with one or more substituents selected from those exemplified for the preferred substituents of the substituted aromatic hydrocarbon group having 6 to 14 carbon atoms of G² (including a case where both are substituted).

39) In the formula (I), when A¹ is —(CH₂)₃—, A¹-A²-G¹ links in the form of A¹-C(═O)—NH-G¹, and G¹ represents a single bond, it is preferable that A³-A⁴-G² as a whole is a heterocyclic substituted alkyl group consisting of a acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms and a heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring.

40) In the formula (I), when A¹ is —(CH₂)₃—, A¹-A²-G¹ links in the form of A¹-C(═O)—NH-G¹, and G¹ represents a single bond, it is preferable that A³-A⁴-G² as a whole is a heterocyclic substituted alkyl group consisting of a acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms and a heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring. However, in the heterocyclic substituted alkyl group as A³-A⁴-G², a acyclic aliphatic hydrocarbon group portion having 1 to 6 carbon atoms is further preferably substituted with one or more substituents selected from those exemplified for the preferred substituents of the substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms of A³, or a heterocyclic group portion is further preferably substituted with one or more substituents selected from those exemplified for the preferred substituents of the heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, of G² (including a case where both are substituted).

41) In the formula (I), when all of A¹, A², G¹, A³, and A⁴ represent a single bond, G² is preferably a hydrogen atom or a acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms.

Also, the preferred combinations of X, A¹, A², G¹, A³, A⁴ and G² in formula (I) as described in above 1) through 41) are more preferably combined with a preferred group represented by R²-A⁵-, exemplified as preferred combinations of R and A⁵, that is R²-A⁵-group in which A⁵ is a single bond and R² is a substituted or unsubstituted monocyclic C₃-C₅ aromatic heterocyclic group having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring, or R²-A⁵-group in which R² is a substituted or unsubstituted aliphatic hydrocarbon group, and with a preferred group represented by R³-A⁶-, exemplified as preferred combinations of R³ and A⁶.

The pyrrolopyrimidinone derivative of the formula (I) has tautomeric forms represented by the following

[wherein A¹, A², A³, A⁴, A⁵, A⁶, G¹, G², R², and R³ are the same as those defined above in the formula (I).]

However, needless to say all such tautomeric forms are within the scope of the present invention.

When one or more asymmetric structures exist on atoms constituting molecules of the pyrrolopyrimidinone derivative formula (I), optically active forms of the respective asymmetric structures and their mixtures combined in an arbitrary ratio are also within the scope of the present invention.

When there exist stereochemical isomers of molecules of the pyrrolopyrimidinone derivative of formula (I), the stereochemical isomers and their combinations in any are also within the scope of the present invention.

The pyrrolopyrimidinone derivative of the formula (I) may have a basic group in its molecules. In this case, if necessary, it can be converted into pharmaceutically acceptable acid addition salts. Such acids include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and carbonic acid; or organic acids such as acetic acid, citric acid, malic acid, oxalic acid, tartaric acid, lactic acid, maleic acid, fumaric acid, and methanesulfonic acid.

The pyrrolopyrimidinone derivative of formula (I) may have an acidic group in its molecules. In this case, when required, the acidic group may be converted into pharmaceutically acceptable salts, including non-toxic cation salts, exemplified by alkali metal ions such as Na⁺ or K⁺, alkaline earth metal ions such as Mg²⁺ or Ca²⁺, metal ions such as Al³⁺ or Zn²⁺, ammonia, and salts with an organic base such as triethylamine, ethylenediamine, propanediamine, pyrrolidine, piperidine, piperazine, pyridine, lysine, choline, ethanolamine, N,N-dimethylethanolamine, 4-hydroxypiperidine, glucosamine, or N-methylglucamine.

In the formula (II), A¹, A², A³, A⁴, A⁵, A⁶, G¹, G², R², and R³ are the same as those defined above in the formula (I), and examples thereof include the same as those exemplified in the formula (I), respectively. Also preferred examples of A¹, A², A³, A⁴, A⁵, A⁶, G¹, G², R² and R³ and preferred combinations of them are the same as those described for the pyrrolopyrimidinone derivative of the present invention represented in the formula (I) except those being obstacle on the chemical reaction in both of the reaction from the pyrrolopyrimidine derivative of the present invention represented by the formula (I) to the pyrrolopyrimidinone derivative of the present invention represented by the formula (I), and the reaction from the pyrrolopyrimidine derivative represented by the formula (II) to the pyrrolopyrimidinone derivative of the present invention represented by the formula (I).

In the formula (II), X¹ represents a chlorine atom, a bromine atom, an iodine atom, a C₂-C₁₀ acylthio group, a C₂-C₈ alkoxymethylthio group, a C₁-C₈ alkyl group or a C₁-C₈ arylsulfonyloxy group, but an explanation will be given below of the case where X¹ represents a chlorine atom, a bromine atom, an iodine atom, or a C₁-C₈ alkyl or arylsulfonyloxy group. When X¹ represents a C₁-C₈ alkyl or arylsulfonyloxy group, examples of the C₁-C₈ alkyl or arylsulfonyloxy group include sulfonyloxy group consisting optionally substituted C₁-C₈ alkyl or aryl group and sulfonyl group, such as methylsulfonyloxy, trifluoromethylsulfonyloxy, ethylsulfonyloxy, propylsulfonyloxy, butylsulfonyloxy, t-butylsulfonyloxy, nonafluorobutylsulfonyloxy, phenylsulfonyloxy, p-bromophenylsulfonyloxy, p-toluylsulfonyloxy, benzylsulfonyloxy, α-phenethylsulfonyloxy and β-phenethylsulfonyloxy. Examples of such preferred X¹ include a chlorine atom, a bromine atom, an iodine atom and a trifluoromethylsulfonyloxy group. Particularly, a chlorine atom or a trifluoromethylsulfonyloxy group is more preferred.

From the compounds represented by the formula (Ic), the pyrrolopyrimidinone derivative of formula (I) of the present invention can be easily manufactured based on the technical common sense of the person skilled in the art.

In the formula (Ic), A¹, A², A³, A⁴, A⁵, A⁶, G¹, G², R², and R³ are the same as those defined above in formula (I), and examples thereof include the same as those exemplified in formula (I), respectively.

In the formula (Ic), Q represents a C₂-C₁₀ acyl group, a C₂-C₁₀ alkoxymethyl group, or a substituted or unsubstituted benzyl group. When Q represents a C₂-C₁₀ acyl group, examples of the C₂-C₁₀ acyl group include acetyl, trifluoroacetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, benzoyl, phenylacetyl, phenylpropionyl, cinnamoyl. When Q represents a C₂-C₁₀ alkoxymethyl, examples of the C₂-C₁₀ alkoxymethyl group include methoxymethyl, methoxyethoxymethyl, t-butoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzyloxymethyl, p-methoxybenzyloxymethyl, p-nitrobenzyl-oxymethyl, o-nitrobenzyloxymethyl and 4-methoxyphenoxymethyl. When Q represents a substituted or unsubstituted benzyl group, examples of the substituted or unsubstituted benzyl group include benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl and p-cyanobenzyl. Examples of such preferred Q include 2-(trimethylsilyl)ethoxymethyl.

The pyrrolopyrimidinone derivative of the formula (I) can be prepared from pyrrolo[3,2-d]pyrimidine derivative of the formula (II) by the following synthesis (A).

Note that, the pyrrolopyrimidinone derivative represented by the formula (I) is described as (Ia) in the following synthesis and is sometimes expressed as a pyrrolo[3,2-d]pyrimidine derivative. [wherein R^1A represents a group capable of withstanding a conversion reaction among groups defined to be represented by A¹-A²-G¹-A³-A⁴-G² in formula (I). R^2A represents a group capable of withstanding a conversion reaction among groups defined to be represented by R²-A⁵ in formula (I). R^3A represents a group capable of withstanding a conversion reaction among groups defined to be represented by R³-A⁶ in formula (I). X¹⁰ represents a chlorine atom, a bromine atom, an iodine atom, or an optionally substituted C₁-C₈ alkyl or arylsulfonyloxy group.]

In other words, the pyrrolopyrimidinone derivative Ia-A) of the present invention can be synthesized by hydrolysis of the pyrrolo[3,2-d]pyrimidine derivative (II-A). In this hydrolysis reaction, the reaction is performed by using a base such as a sodium hydroxide or a lithium hydroxide and using a solvent such as dioxane, ethanol, 2-propanol, or dimethyl sulfoxide at a temperature in a range of 0° C. to 150° C.

Among the pyrrolo[3,2-d]pyrimidine derivatives of formula (II), a pyrrolo[3,2-d]pyrimidine derivative of formula (II-B) can be synthesized from the pyrrolo[3,2-d]pyrimidine derivative of formula (Ia) by the following synthesis.

[wherein R^1B represents a group capable of withstanding a conversion reaction among groups defined to be represented by A¹-A²-G¹-A³-A⁴-G² in formula (I). R^2B represents a group capable of withstanding a conversion reaction among groups defined to be represented by R²-A⁵ in formula (I). R^3B represents a group capable of withstanding a conversion reaction among groups defined to be represented by R³-A⁶ in formula (I). X¹⁰ has the same meaning as defined above.]

In other words, when X¹⁰ is a chlorine atom, the pyrrolopyrimidinone derivative (II-B) of the present invention can be synthesized by reacting the pyrrolopyrimidinone derivative (Ia-B) of the present invention with phosphorus oxychloride. In the chlorination using phosphorus oxychloride, the reaction is carried out in a solvent such as acetonitrile under general chlorination reaction conditions, for example, in the presence or absence of a solvent such as triethylamine, 4-dimethylaminopyridine or dimethyl type aniline, at a temperature in a range of 0° C. to 150° C.

Also, when X¹⁰ is a trifluoromethanesulfonyloxy group, the pyrrolopyrimidinone derivative (II-B) of the present invention can be synthesized by reacting the pyrrolopyrimidinone derivative (Ia-B) of the present invention with trifluoromethanesulfonic anhydride. In trifluoromethane sulfonyloxylation using trifluoromethane sulfonic anhydride, the reaction can be carried out together with pyridine or amines such as triethylamine in the presence or absence of a solvent such as dichloromethane at a temperature in a range of 0° C. to 100° C.

Among the pyrrolo[3,2-d]pyrimidine derivatives of formula (Ia-B), the pyrrolo[3,2-d]pyrimidine derivative of formula (Ia-B1) can be synthesized from the 7-cyanopyrrolo[3,2-d]pyrimidine derivative of the formula (Ia-CN) by the following synthesis (B1).

[wherein R^1B1 represents a group capable of withstanding a conversion reaction among groups defined to be represented by A¹-A²-G¹-A³-A⁴-G² in the formula (I). R^2B1 represents a group capable of withstanding a conversion reaction among groups defined to be represented by R²-A⁵ in the formula (I).]

In other words, the pyrrolopyrimidinone derivative (Ia-B1) of the present invention can be synthesized by the hydrolyzing pyrrolo[3,2-d]pyrimidine derivative (Ia-CN). The hydrolysis reaction is carried out using a base such as sodium hydroxide or lithium hydroxide in a solvent such as ethanol, 2-propanol or dimethylsulfoxide in the presence or absence of hydrogen peroxide at a temperature in a range of 0° C. to 100° C.

Among the pyrrolo[3,2-d]pyrimidine derivatives of the formula (Ia-B), a pyrrolo[3,2-d]pyrimidine derivative of the formula (Ia-B2) can be synthesized from the pyrrolo[3,2-d]pyrimidine derivative of the formula (Ia-B1) by the following synthesis (B2).

[wherein R^1B2 represents a group capable of withstanding a conversion reaction among groups defined to be represented by A¹-A²-G¹-A³-A⁴-G² in formula (I). R^2B2 represents a group capable of withstanding a conversion reaction among groups defined to be represented by R²-A⁵ in formula (I).]

In other words, the pyrrolopyrimidinone derivative (Ia-B2) of the present invention can be synthesized by performing a Hoffmann rearrangement on the pyrrolopyrimidinone derivative (Ia-B1) of the present invention. The Hoffmann rearrangement is carried out in a solvent such as ethanol, 2-propanol, acetonitrile or water, using a reagent such as sodium hypochlorite, bromine, or benzyltrimethyl ammonium tribromide in the presence or absence of a base such as sodium hydroxide at a temperature of 0° C. to 150° C.

Among the pyrrolo[3,2-d]pyrimidine derivatives of formula (Ia-B), a pyrrolo[3,2-d]pyrimidine derivative of formula (Ia-B3) can be synthesized from the pyrrolo[3,2-d]pyrimidine derivative of formula (Ia-B2) by the following synthesis (B3).

[wherein R^1B3 represents a group capable of withstanding a conversion reaction among groups defined to be represented by A¹-A²-G¹-A³-A⁴-G² in the formula (I). R^2B3 represents a group capable of withstanding a conversion reaction among groups defined to be represented by R²-A⁵ in the formula (I). R^3B3 represents a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.]

In other words, the pyrrolopyrimidinone derivative (Ia-B3) of the present invention can be synthesized by reacting the pyrrolopyrimidinone derivative (Is-B2) of the present invention with nitrous acid or nitrite ester and performing a Sandmayer reaction. In the Sandmayer reaction using nitrous acid or nitrite ester, reagents, for example, nitrous acid, sodium nitrite, isoamyl nitrite, or t-butyl nitrite is used, and the reaction can be performed in the presence of halogenation reagents, for example hydrofluoric acid or fluoroboric acid for fluorination, for example copper chloride or carbon tetrachloride for chlorination, for example carbon tetrabromide or bromoform for bromination, and diiodomethane or iodine for iodination, in the presence or absence of an acid such as sulfuric acid or hydrochloric acid, in the presence or absence of an acid such as sulfuric acid or hydrochloric acid, by using or without using a solvent such as ethanol, acetonitrile or water, at a temperature in a range of 0° C. to 150° C.

Among the pyrrolo[3,2-d]pyrimidine derivatives of formula (Ia-B), a pyrrolo[3,2-d]pyrimidine derivative of formula (Ia-B4) can be synthesized from the pyrrolo[3,2-d]pyrimidine derivative of formula (Ia-B2) by the following synthesis (B4).

[wherein R^1B4 represents a group capable of withstanding a conversion reaction among groups defined to be represented by A¹-A²-G¹-A³-A⁴-G² in the formula (I). R^2B4 represents a group capable of withstanding a conversion reaction among groups defined to be represented by R²-A⁵ in the formula (I).]

In other words, the pyrrolopyrimidinone derivative (Ia-B4) of the present invention can be synthesized by reacting the pyrrolopyrimidinone derivative (Ia-B2) of the present invention with nitrous acid or nitrite ester. The reaction using nitrous acid or nitrite ester can be performed by using nitrous acid, sodium nitrite, isoamyl nitrite, or t-butyl nitrite as a reagent, in the presence of or in the absence of an acid such as sulfuric acid or hydrochloric acid in the presence of dimethylformamide, tetrahydrofuran, ethanol or water as a solvent, at a temperature in a range of 0° C. to 150° C.

Among the pyrrolo[3,2-d]pyrimidine derivatives of formula (Ia-B), a pyrrolo[3,2-d]pyrimidine derivative of formula (Ia-B5) can be synthesized from the pyrrolo[3,2-d]pyrimidine derivative of formula (Ia-B4) by the following synthesis (B5).

[wherein R^1B5 represents a group capable of withstanding a conversion reaction among groups defined to be represented by A¹-A²-G¹-A³-A⁴-G² in the formula (I). R^2B5 represents a group capable of withstanding a conversion reaction among groups defined to be represented by R²-A⁵ in the formula (I).]

In other words, the pyrrolopyrimidinone derivative (Ia-B5) of the present invention can be synthesized by reacting nitric acid or nitrogen dioxide with the pyrrolopyrimidinone derivative (Ia-B4) of the present invention. The reaction using nitric acid or nitrogen dioxide can be performed by using nitric acid, nitrogen dioxide, cerium ammonium nitrate or sodium nitrite as a reagent, in the presence or absence of sulfuric acid, hydrochloric acid, acetic acid or ozone, in the presence of dichloroethane, dichloromethane, acetonitrile or water as a solvent, at a temperature in a range of 0° C. to 100° C.

Among the pyrrolo[3,2-d]pyrimidine derivatives of formula (Ia-B), a pyrrolo[3,2-d]pyrimidine derivative of formula (Ia-B6) can be synthesized from the pyrrolo[3,2-d]pyrimidine derivative of formula (Ia-B6a) by the following synthesis (B6).

[wherein R^1B6 represents a group capable of withstanding a conversion reaction among groups defined to be represented by A¹-A²-G¹-A³-A⁴-G² in the formula (I). R^2B6 represents a group capable of withstanding a conversion reaction among groups defined to be represented by R²-A⁵ in the formula (I). R^3B6a is a bromine atom or iodine atom, and among groups defined as R³ in the formula (I), R^3B6 is a substituted or unsubstituted saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms, a substituted or unsubstituted alicyclic hydrocarbon group having 3 to 8 carbon atoms, a substituted or unsubstituted aromatic hydrocarbon group having 6 to 14 carbon atoms, a monocyclic C₃-C₅ aromatic heterocyclic group having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on the substituted or unsubstituted ring, or a trimethylsilyl.]

In other words, the pyrrolopyrimidinone derivative (Ia-B6) of the present invention can be synthesized by reacting the pyrrolopyrimidinone derivative (Ia-B6a) of the present invention with a terminal alkyne derivative represented by formula R^3B6—C≡C—H in the presence of a catalytic amount of palladium. The reaction with the terminal alkyne derivative using the catalytic amount of palladium is carried out using the terminal alkyne derivative together with a palladium catalyst, e.g., tetrakis(triphenylphosphine) palladium, chlorobis(triphenylphosphine) palladium, or palladium acetate, in the presence or absence of a ligand, such as triphenylphosphine, tri(o-tolyl)phosphine, or 1,1′-bis(diphenylphosphino)ferrocene, in the presence or absence of a catalytic amount of copper salts, e.g., copper iodide or copper bromide, in the presence of a base such as triethylamine, diethylamine, piperizine or pyrrolidine, using solvents such as tetrahydrofuran, dimethylformamide, and toluene, at a temperature in a range of 0° C. to 150° C.

Among the pyrrolo[3,2-d]pyrimidine derivatives of the formula (Ia-B), a pyrrolo[3,2-d]pyrimidine derivative of formula (Ia-B7) can be prepared from the pyrrolo[3,2-d] pyrimidine derivative of formula (Ia-B7a) by the following synthesis (B7).

[wherein R^1B7 represents a group capable of withstanding a conversion reaction among groups defined to be represented by A¹-A²-G¹-A³-A⁴-G² in the formula (I). R^2B7 represents a group capable of withstanding a conversion reaction among groups defined to be represented by R²-A⁵ in the formula (I). R^3B7a is a bromine atom or an iodine atom. R^3B7 is a substituted or unsubstituted aromatic hydrocarbon group having 6 to 14 carbon atoms, or an aromatic heterocyclic group having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on the substituted or unsubstituted ring among groups defined as R³ in the formula (I).]

In other words, the pyrrolopyrimidinone derivative (Ia-B7) of the present invention can be synthesized, in the presence of a catalytic amount of palladium, by adding a boric acid derivative [R^3B7—B(OR)₂, wherein R^3B7 is the same as defined above in the synthesis (B7), and R represents a hydrogen atom or an alkyl group] to the pyrrolopyrimidinone derivative (Ia-B7a) of the present invention. That is, in the reaction with the boric acid derivative using the catalytic amount of palladium, the reaction can be performed by using, together with the boric acid derivative, a palladium catalyst, for example, chlorobis(triphenylphosphine) palladium, palladium acetate, and tris(dibenzylideneacetone)dipalladiumu-chloroform adduct in the presence or absence of a ligand, such as triphenylphosphine, tri(o-tolyl)phosphine, or 1,1′-bis(diphenylphosphino)ferrocene, in the presence of base such as potassium phosphate, sodium carbonate, potassium hydroxide, or sodium ethoxide, using a solvent such as tetrahydrofuran, dimethylformamide, 2-propanol and water, at a temperature in a range of 0° C. to 150° C.

Among the pyrrolo[3,2-d]pyrimidine derivatives of formula (Ia-B), a pyrrolo[3,2-d]pyrimidine derivative of formula (Ia-B8) can be synthesized from the pyrrolo[3,2-d] pyrimidine derivative of formula (Ib-B8a) by the following synthesis (B8).

[wherein R^1B8 represents a group capable of withstanding a conversion reaction among groups defined to be represented by A¹-A²-G¹-A³-A⁴-G² in the formula (I). R^2B8 represents a group capable of withstanding a conversion reaction among groups defined to be represented by R²-A⁵ in the formula (I). R^3B8a is a bromine atom or an iodine atom, and R^3B8 is a group defined as R³ in the formula (I).]

In other words, the pyrrolopyrimidinone derivative (Ia-B8) of the present invention can be synthesized by reacting a terminal alkene derivative upon the pyrrolopyrimidinone derivative (Ia-B8a) of the present invention in the presence of a catalytic amount of palladium. That is, in the reaction with a terminal alkene derivative using the catalytic amount of palladium, the reaction can be performed by using, together with the terminal alkene derivative, a palladium catalyst, for example, palladium chloride, palladium acetate, or tris(dibenzylideneacetone)dipalladium-chloroform adduct in the presence or absence of a ligand, such as triphenylphosphine, tri(o-tolyl)phosphine, or 1,1′-bis(diphenylphosphino) ferrocene, in the presence of a base such as a potassium phosphate, potassium carbonate or triethylamine, and using a solvent such as tetrahydrofuran, dimethylformamide or water, at a temperature in a range of 0° C. to 150° C.

Alternatively, the pyrrolopyrimidinone derivative (Ia-B8) of the present invention can also be synthesized by performing a catalytic semi-reduction or hydroboration-protonation on the pyrrolo[3,2-d]pyrimidine derivative (Ia-B6) having an alkynyl group prepared by the Synthesis (B6). For example, the catalytic semi-reduction is performed using a solvent such as methanol, ethanol or tetrahydrofuran, in the presence of a palladium catalyst, e.g., palladium-barium sulfate-quinoline, palladium-activated carbon-quinoline, under a hydrogen atmosphere, at a temperature in a range of 0° C. to 100° C. The hydroboration-protonation is performed such that hydroboratino is performed using a hydroborating reagent, e.g., 9-borabicyclo[3.3.1]nonane or dicyclohexylborane, and protonation is then performed using acetic acid. The reaction can be performed using a solvent such as tetrahydrofuran, diethylether, methylenedichloride, or toluene, at a temperature in a range of 0° C. to 100° C.

Among the pyrrolo[3,2-d]pyrimidine derivatives of formula (Ia-B), a pyrrolo[3,2-d]pyrimidine derivative of formula (Ia-B9) can be synthesized from the pyrrolo [3,2-d]pyrimidine derivative of formula (Ia-B9a) by the following synthesis (B9).

[wherein R^1B9 represents a group capable of withstanding a conversion reaction among groups defined to be represented by A¹-A²-G¹-A³-A⁴-G² in formula (I). R^2B9 represents a group capable of withstanding a conversion reaction among groups defined to be represented by R²-A⁵ in formula (I). R^3B9a is a bromine atom or an iodine atom. R^3B9 is a substituted or unsubstituted saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms, substituted or unsubstituted C₁-C₁₀ alicyclic hydrocarbon group, or a vinyl group.]

In other words, the pyrrolopyrimidinone derivative (Ia-B9) of the present invention can be synthesized by reacting an organometallic reagent to the pyrrolopyrimidinone derivative (Ia-B9a) of the present invention using a catalytic amount of palladium or nickel. For example, in the reaction with the organometallic reagent using the catalytic amount of palladium or nickel, an organozinc reagent, e.g., phenylzinc chloride or an organozinc compound prepared from a Grignard reagent and zinc chloride, an organotin reagent, e.g., phenyltrimethyltin or tetramethyltin can be used. As the Grignard reagent, organometallic reagents, such as phenylbromomagnesium or n-butylbromomagnesium, can be used. Useful examples of the palladium catalyst include tetrakis(triphenylphosphine) palladium, tris(dibenzylidene-acetone)dipalladium-chloroform adduct, chloro{1,1′-bis (diphenylphosphino)ferrocene}palladium, and the like. Useful examples of the nickel catalyst include chloro{1,3-bis (diphenylphosphino)propane}nickel or nickel bromide. The reaction can be performed using a solvent such as diethylether, tetrahydrofuran or dimethylformamide, in the presence or absence of a ligand, such as triphenylphosphine, tri(o-tolyl)phosphine, or 1,1′-bis(diphenylphosphino) ferrocene, at a temperature in a range of 0° C. to 150° C.

The pyrrolopyrimidinone derivative (Ia-B9) can also be synthesized through hydrogen reduction of the pyrrolo[3,2-d]pyrimidine derivative (Ia-B6) having an alkynyl group prepared by the synthesis (B6) or the pyrrolo[3,2-d]pyrimidine derivative (Ia-B8) having an alkenyl group prepared by the synthesis (B8). The hydrogen reduction is performed using a solvent such as methanol, ethanol or tetrahydrofuran in the presence of a catalytic amount of palladium-activated carbon under a hydrogen atmosphere at a temperature in a range of 0° C. to 100° C.

Among the pyrrolo[3,2-d]pyrimidine derivatives of formula (Ia-B), a pyrrolo[3,2-d]pyrimidine derivative of formula (Ia-B10) can be synthesized from the pyrrolo[3,2-d] pyrimidine derivative of formula (Iz-10a) by the following synthesis (B10).

[wherein R^1B10 represents a group capable of withstanding a conversion reaction among groups defined to be represented by A¹-A²-G¹-A³-A⁴-G² in the formula (I) R^2B10 represents a group capable of withstanding a conversion reaction among groups defined to be represented by R²-A⁵ in the formula (I). R^3B10a is a bromine atom or an iodine atom. R^3B10 is a C₂-C₁₀ hydroxyl, alkoxy, N-substituted amino or N,N-disubstituted amino group.

In other words, the pyrrolopyrimidinone derivative (Ia-B10) of the present invention can be synthesized by reacting the pyrrolopyrimidinone derivative (Ia-B10a) of the present invention with carbon monoxide in the presence of a catalytic amount of palladium. For example, the carbonyl insertion reaction using a catalytic amount of palladium is performed under a carbon monoxide atmosphere, using a palladium catalyst, e.g., tetrakis(triphenylphosphine) palladium, palladium acetate, or tris(dibenzylideneacetone)dipalladium-chloroform adduct, in the presence or absence of a ligand, e.g., triphenylphosphine, tri(o-tolyl)phosphine, or 1,1′-bis(diphenylphosphino)ferrocene, in the presence or absence of a base, e.g., potassium carbonate, or triethylamine. A solvent such as acetonitrile, tetrahydrofuran, or dimethylformamide is used, and the reaction is carried out at a temperature ranging between 0° C. and 150° C. In this case, addition of water as a reacting agent gives a compound with a carboxy group, and addition of an alcohol gives a compound with an alkoxycarbonyl group. Addition of a primary or secondary amine gives a compound with N-substituted or N,N-disubstituted aminocarbonyl group.

Among the pyrrolo[3,2-d]pyrimidine derivatives of formula (Ia-B), a pyrrolo[3,2-d]pyrimidine derivative of formula (Ia-B11) can be synthesized from the pyrrolo [3,2-d]pyrimidine derivative of formula (Ia-11a) by the following synthesis (B11).

[wherein R^1B11 represents a group capable of withstanding a conversion reaction among groups defined to be represented by A¹-A²-G¹-A³-A⁴-G² in the formula (I). R^2B11 represents a group capable of withstanding a conversion reaction among groups defined to be represented by R²-A⁵ in the formula (I). R^2B11a is a bromine atom or an iodine atom.]

In other words, the pyrrolopyrimidinone derivative (Ia-B11) of the present invention can be synthesized by reacting the pyrrolo[3,2-d]pyrimidine derivative (Ia-B11a) of the present invention under a carbon monoxide atmosphere in the presence of a reducing agent and a catalytic amount of palladium. For example, the formylation reaction using a catalytic amount of palladium is performed under the carbon monoxide atmosphere. Useful examples of the palladium catalyst include tetrakis(triphenylphosphine) palladium, palladium acetate, tris(dibenzylideneacetone)dipalladium-chloroform adduct. The reaction is performed using a solvent such as acetonitrile, tetrahydrofuran, or dimethylformamide in the presence or absence of a ligand such as triphenylphosphine or tri(o-tolyl)phosphine or 1,1′-bis(diphenylphosphino) ferrocene in a temperature range of 0° C. to 150° C. The reaction is performed in the presence of or in the absence of a base such as potassium carbonate or triethylamine. Addition of a reducing agent such as tributyltin hydride or triethylsilane gives a compound with a formyl group, and addition of an organometallic agent such as alkyl zinc, alkyl boron or an organotin reagent give a compound with an alkylcarbonyl group.

Among the pyrrolo[3,2-d]pyrimidine derivatives of formula (Ia-B), a pyrrolo[3,2-d]pyrimidine derivative of formula (Ia-B12) can be synthesized from the pyrrolo [3,2-d]pyrimidine derivative of formula (Ia-B12a) by the following synthesis (B12).

[wherein R^1B12 represents a group capable of withstanding a conversion reaction among groups defined to be represented by A¹-A²-G¹-A³-A⁴-G² in the formula (I). R^2B12 represents a group capable of withstanding a conversion reaction among groups defined to be represented by R²-A⁵ in the formula (I). R^3B12a is a bromine atom or an iodine atom.]

In other words, the pyrrolopyrimidinone derivative (Ia-B12) of the present invention can be synthesized by reacting the pyrrolopyrimidinone derivative (Ia-B12a) of the present invention with a trifluoromethyl donating reagent. That is, in the trifluoromethylation reaction, the reaction can be performed by utilizing various methods, for example, a method using copper (I) iodide or cesium fluoride together with a trifluoromethyl donator such as sodium trifluoroacetate or trifluoromethyl acetate, a method for preparing a trifluoromethyl copper compound from a trifluoromethyl zinc compound or a trifluoromethyl cadmium compound and copper (I) bromide, or a method for preparing a trifluoromethyl copper compound from a trifluoromethyl iodide and copper powder, by using a solvent such as dimethylformamide, N-methylpyrrolidinone, hexamethylphosphoramide, acetonitrile, or pyridine, at a temperature in a range of 0° C. to 150° C.

Among the pyrrolo[3,2-d]pyrimidine derivatives of formula (Ia-B), a pyrrolo[3,2-d]pyrimidine derivative of Formula (Ia-B13) can be synthesized from the pyrrolo [3,2-d]pyrimidine derivative of Formula (Ia-B13a) by the following synthesis (B13).

[wherein R^1B13 represents a group capable of withstanding a conversion reaction among groups defined to be represented by A¹-A²-G¹-A³-A⁴-G² in the formula (I). R^2B13 represents a group capable of withstanding a conversion reaction among groups defined to be represented by R²-A⁵ in the formula (I).]

The pyrrolopyrimidinone derivative (Ia-B13) of the present invention can be synthesized by reacting the pyrrolopyrimidinone derivative (Ia-B13a) of the present invention with water in the presence of nitrous acid. That is, the hydroxylation reaction in the presence of nitrous acid is performed using sodium nitrite or isoamyl nitrite in the presence of trifluoroacetic acid or sulfuric acid. The reaction can be performed using water as a solvent in the presence or absence of a cosolvent such as acetonitrile or dimethylformamide, at a temperature in a range of 0° C. to 150° C.

Among the pyrrolo[3,2-d]pyrimidine derivatives of formula (Ia-B), a pyrrolo[3,2-d]pyrimidine derivative of formula (Ia-B14) can be synthesized from the pyrrolo [3,2-d]pyrimidine derivative of formula (Ia-B14a) by the following synthesis (B14).

[wherein R^1B14 represents a group capable of withstanding a conversion reaction among groups defined to be represented by A¹-A²-G¹-A³-A⁴-G² in the formula (I). R^2B14 represents a group capable of withstanding a conversion reaction among groups defined to be represented by R²-A⁵ in the formula (I). R^3B14 is a C₁-C₆ aliphatic hydrocarbon group.]

In other words, the pyrrolopyrimidinone derivative (Ia-B14) of the present invention can be synthesized by reacting the pyrrolopyrimidinone derivative (Ia-B14a) of the present invention with water in the presence of nitrous acid. That is, the alkylthioration reaction in the presence of nitrous acid is performed using sodium nitrite or isoamyl nitrite in the presence or absence of acids such as hydrochloric acid or sulfuric acid. The reaction is carried out using dialkyldisulfide or alkanethiol as a reagent in a solvent such as acetonitrile or dimethylformamide at a temperature in a range of 0° C. to 150° C.

Among the pyrrolo[3,2-d]pyrimidine derivatives represented by (Ia-B) of the synthesis (B) or (Ib-CN) of the synthesis (B1), a pyrrolo[3,2-d]pyrimidine derivative of formula (Ia-C2) can be synthesized from the pyrrolo [3,2-d]pyrimidine derivative of formula (Ia-C1) by the following synthesis (C).

[wherein R^1C represents a group capable of withstanding a conversion reaction among groups defined to be represented by A¹-A²-G¹-A³-A⁴-G² in the formula (I). R^2C1 is a chlorine atom or a bromine atom. R^3C represents a cyano group or a group capable of withstanding a conversion reaction among groups defined to be represented by R²-A⁵ in the formula (I). When A⁵ is —NR²⁰¹— (R²⁰¹ is the same as defined above for R²⁰¹ in the formula (1)), R^2C2 is as defined to exclude a fluorine atom, a chlorine atom, a bromine atom and an iodine atom from groups defined for R² in formula (I). Also, when A⁵ is a single bond, R^2C2 is a heterocyclic group having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on the substituted or unsubstituted ring in which R^2C2 is linked to A⁵ on a nitrogen atom.

In other words, the pyrrolopyrimidinone derivatives (Ia-C2) can be synthesized by reacting the pyrrolopyrimidinone derivatives (Ia-C1) of the present invention with a primary or secondary amine. Amination using the primary or secondary amine is performed without the use of a solvent or with the use of a solvent such as dimethylsulfoxide, dimethylformamide, dioxane, tetrahydrofuran or toluene in the presence or absence of a base such as pyridine, triethylamine, diisopropylethyl-amine, 4-dimethylaminopyridine or sodium carbonate. The reaction is performed in the presence or absence of a transition metal complex catalyst prepared by mixing a palladium salt such as palladium acetate with a phosphorus ligand such as triphenylphosphine, at a temperature in a range of 0° C. to 150° C.

Among the pyrrolo[3,2-d]pyrimidine derivatives represented by the formula (Ia) or (Ia-CN) of the synthesis (B1), a pyrrolo[3,2-d]pyrimidine derivative of formula (Ia-D2) can be synthesized from the pyrrolo[3,2-d]pyrimidine derivative of formula (Ia-D1) by the following synthesis (D).

[wherein R^1D represents a group capable of withstanding a conversion reaction among groups defined to be represented by A¹-A²-G¹-A³-A⁴-G² in the formula (I). R^2D1 is a chlorine atom or a bromine atom. R^2D2 is a substituted or unsubstituted aromatic hydrocarbon group having 6 to 14 carbon atoms, or an aromatic heterocyclic group having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom on the substituted or unsubstituted ring. R^3D is a cyano group or a group capable of withstanding a conversion reaction among groups defined to be represented A⁶-R³ in the formula (I).]

In other words, the pyrrolopyrimidinone derivative (Ia-D2) of the present invention can be synthesized by reacting the pyrrolopyrimidinone derivative (Ia-D1) of the present invention with, for example, a boric acid derivative represented by R^2D2—B(OR)₂ [in which R^2D2 is as defined above in the synthesis (D), and R is a hydrogen atom or an alkyl group). The reaction with the boric acid derivative is performed under general Suzuki reaction conditions, for example, at a temperature in a range of 0° C. to 150° C. using a solvent such as 2-propanol and/or water in the presence of an inorganic base such as sodium carbonate, by using a catalyst such as palladium acetate, and adding a ligand such as triphenylphosphine.

Among the pyrrolo[3,2-d]pyrimidine derivatives of Formula (Ia) or (Ia-CN) prepared in the synthesis (B1), a pyrrolo[3,2-d]pyrimidine derivative of formula (Ia-E2) can be synthesized from the pyrrolo[3,2-d]pyrimidine derivative of formula (Ia-E1) in the following manner shown in Synthesis (E):

[wherein R^1E represents a group capable of withstanding a conversion reaction among groups defined to be represented by A¹-A²-G¹-A³-A⁴-G² in the formula (I). R^2E is a chlorine atom, a bromine atom or an iodine atom. R^3E is a cyano group or a group capable of withstanding a conversion reaction among groups defined to be represented by A⁶-R³.]

In other words, the pyrrolopyrimidinone derivative (Ia-E2) of the present invention can be synthesized by halogenation of the pyrrolopyrimidinone derivative (Ia-E1) of the present invention. The halogenation is performed using a halogenation reagent such as N-chlorosuccinic imide or N-bromosuccinic imide in the presence of a solvent such as dimethylformamide, dioxane or tetrahydrofuran at a temperature in a range of −20° C. to 150° C.

Among the pyrrolo[3,2-d]pyrimidine derivatives of Formula (Ia) or (Ia-CN) prepared in the synthesis (B1), a pyrrolo[3,2-d]pyrimidine derivative of formula (1a-F) given below can be synthesized from the pyrrol derivative of formula (IV-F) in the following manner shown in Synthesis (F)

[wherein R^1F represents a group capable of withstanding a conversion reaction among groups defined to be represented by A¹-A²-G¹-A³-A⁴-G² in the formula (I). R^2F represents, among the groups defined for R² in the formula (I), groups excluding a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, and a substituted or unsubstituted heterocyclic group that is bonded with a carbon atom and a nitrogen atom of a pyrrole ring to which R^2F is bonded, and having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring. R^3F is a cyano group or a group capable of withstanding a conversion reaction among groups defined to be represented by A⁶-R³ in formula (I).]

In other words, the pyrrolo[3,2-d]pyrimidine derivative of the formula (Ia-F) of the present invention can be synthesized by performing a cyclization reaction using formamidine or formamide on the pyrrole derivative of formula (IV-F). The cyclization reaction using formamidine can be performed by using formamidine acetate, for example, in a solvent such as 2-propanol at a temperature in a range of 0° C. to 150° C. The cyclization reaction using formamide can be performed smoothly by using a base such as formamide or sodiummethoxide, in the presence or absence of a solvent such as dimethylsulfoxide or dimethoxyethane at a temperature in a range of 0° C. to 150° C.

The pyrrolo[3,2-d]pyrimidine derivatives of the formula (Ia) or the synthesis (B1) can be synthesized from the pyrrolo [3,2-d]pyrimidine derivative of the Formula (I-G) by the following synthesis (G).

[wherein R^1G represents a group capable of withstanding a conversion reaction among groups defined to be represented by A¹-A²-G¹-A³-A⁴-G² in the formula (I). R^2G represents a group capable of withstanding a conversion reaction among groups defined to be represented by R²-A⁵ in the formula (I). R^3G is a cyano group or a group capable of withstanding a conversion reaction among groups defined to be represented by A⁶-R³ in formula (I). Q is an optionally substituted C₂-C₁₀ acyl group, an optionally substituted a C₂-C₈ alkoxymethyl group, or substituted or unsubstituted benzy group.]

In other words, when for example Q is an acyl group, the pyrrolopyrimidinone derivative (Ib-G) of the present invention can be synthesized by reacting the pyrrolopyrimidinone derivative (I-G) of the present invention with an acyl halide. The acylation reaction using the acyl halide is performed under conventional acylation reaction conditions, for example, in the presence of triethylamine or pyridine, at a temperature in a range of 0° C. to 100° C.

Also, when Q is for example an alkoxymethyl or benzyl group, the pyrrolopyrimidinone derivative (I-G) of the present invention can be synthesized by reacting the pyrrolo[3,2-d]pyrimidine derivative (I-G) of the present invention with an alkoxymethyl halide or a benzyl halide. The reaction using the alkoxymethyl halide or the benzyl halide can be performed in the presence of for example sodium hydride in a temperature range of 0° C. to 100° C.

In the thus obtained pyrrolopyrimidinone derivatives (Ib-G) according to the present invention, conversion reactions known to one skilled in the art can be performed for A¹, A², A³, A⁴, A⁵, A⁶, G¹, G², R² and/or R³. Such pyrrolo[3,2-d] pyrimidine derivatives (Ib-G) can be converted into the pyrrolopyrimidinone derivatives (I-G) of the present invention by performing hydrolysis under a neutral or alkaline condition when Q is an acyl group, or under an acidic condition using, for example, trifluoroacetic acid, when Q is an alkoxymethyl group, or by performing a hydrogen addition reaction when R³ is a benzyl group.

The pyrrolopyrimidinone derivatives or the present invention synthesized by the syntheses (A), (B), (C), (D), (E), (F), and (G) have easily convertible substituents, such as an alkoxycarbonyl group, an acyloxy group, or an aromatic nitro group, they can be easily converted into pyrrolopyrimidinone derivatives or the present invention respectively having a carboxy group, a hydroxy group, and an amino group by performing reactions known to one skilled in the art.

When the pyrrolopyrimidinone derivatives of the present invention synthesized by the synthesis (A), (B), (C), (D), (E), (F), and (G) have a carboxy group, they can be converted into pyrrolopyrimidinone derivatives of the present invention having an alkoxycarbonyl group, a carbamoyl group, and an N-alkylcarbamoyl group by a condensation reaction known to one skilled in the art.

When the pyrrolopyrimidinone derivatives of the synthesized by the synthesis (A), (B), (C), (D), (E), (F), and (G) have an amino group, they can be converted into pyrrolopyrimidinone derivatives of the present invention having an acylamino group or an alkylsulfonylamino group by a condensation reaction well known to one skilled in the art.

Also, when they have an amino group, they can also be converted into pyrrolopyrimidinone derivatives of the present invention having a monoalkylamino or a dialkylamino group by a reductive alkylation reaction known to one skilled in the art.

When the pyrrolopyrimidinone derivatives of the present invention synthesized by the synthesis (A), (B), (C), (D), (E), (F), and (G) have a hydroxy group, they can be converted into pyrrolopyrimidinone derivatives of the present invention having an acyloxy group by a condensation reaction known to one skilled in the art.

When the pyrrolopyrimidinone derivatives of the present invention synthesized by the synthesis (A), (B), (C), (D), (E), (F), and (G) have a formyl group, they can be converted into pyrrolopyrimidinone derivatives of the present invention having an alkylaminomethyl group by a reductive alkylation reaction known to one skilled in the art.

In the synthesis of the pyrrolopyrimidinone derivative of the formula (I), the pyrrole derivatives of formula (IV-F) used as starting materials can be prepared from a 3-alkoxypropene nitrile derivative of formula (VI-H) by the following synthesis (H).

(wherein R^1H represents a group capable of withstanding a conversion reaction among groups defined to be represented by A¹-A²-G¹-A³-A⁴-G² in the formula (I). R^2H represents, among the groups defined for R²-A⁵ in the formula (I), groups excluding a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, and a substituted or unsubstituted heterocyclic group that is bonded with a carbon atom and a nitrogen atom of a pyrrole ring to which R^2H is bonded, and having 1 to 4 atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, in the ring. R^3H is a cyano group or a group capable of withstanding a conversion reaction among groups defined to be represented by A⁶-R³ in formula (I).]

In other words, aminopropenitrile derivatives (V-H) can by synthesized by reacting alkoxypropene nitriles (VI-H) with a primary amine (represented by R¹—NH₂ in which R¹ is as defined above for R¹ prepared by the synthesis (H)). The pyrrole derivatives (IV-H) can be synthesized through a reaction between the aminopropenenitrile derivatives (V-H) and methyl bromoacetate in the presence of a base, or through a cyclization reaction.

The reaction between the alkoxypropene nitrile derivatives (V-H) and the primary amine is performed using a solvent such as methanol, ethanol or 2-propanol at a temperature in a range of 0° C. to 100° C.

The reaction between the alkoxypropenenitrile derivatives (VI-H) and methyl bromoacetate is performed in the presence of a base such as sodium carbonate using a solvent such as acetonitrile at a temperature in a range of 0° C. to 150° C.

In the synthesis of the pyrrolopyrimidinone derivative of the formula (I), among the pyrrole derivatives of the formula (IV-F) used as starting materials, a pyrrole derivative having a hydrogen atom as R^2F can be prepared from 3-oxopropanenitrile derivatives of formula (VII-J) by the following synthesis (J)

[wherein R^1J represents a group which can be converted to A¹-A²-G¹-A³-A⁴-G² in the formula (I), and a group capable of withstanding a conversion reaction. R^3J is a cyano group or a group capable of withstanding a conversion reaction among groups defined to be represented by A⁶-R³ in the formula (I).]

In other words, the aminopropenenitrile derivative (V-J) can be synthesized by reacting the 3-oxopropanenitrile derivative (VII-J) with a primary amine (R¹—NH₂ in which R¹ is as defined above for R¹ prepared by the synthesis (J)). The pyrrole derivatives (IV-J) can be synthesized through a reaction between the aminopropenitrile derivatives (V-J) and methyl bromoacetate in the presence of a base, or through a cyclization reaction.

The reaction between 3-oxopropanenitrile derivative (VII-J) and the primary amine is performed using a solvent such as methanol, ethanol or 2-propanol at a temperature in a range of 0° C. to 100° C.

The reaction between the aminopropenitrile derivative (VI-J) and methyl bromoacetate is performed in the presence of a base such as sodium carbonate using a solvent such as acetonitrile in a temperature range of 0° C. to 150° C.

Alternatively, in the syntheses of the pyrrolopyrimidinone derivative of the formula (I), among the pyrrole derivatives of formula (IV-F) used as starting materials, a pyrrole derivative of formula (IV-F) having a hydrogen atom as R²F can also be prepared by the following synthesis (K):

[wherein R^1K represents a group which can be converted to A¹-A²-G¹-A³-A⁴-G² in the formula (I), and a group capable of withstanding a conversion reaction. R^3K is a cyano or a group capable of withstanding a conversion reaction among groups defined to be represented by A⁶-R³ in formula (I).]

In other words, the aminopropenitrile derivative (V-K) can by synthesized by reacting the 3-oxopropanenitrile derivative (VII-K) and a glycinemethylester derivative (R¹—NH—CH₂—COOCH₃ having R¹ on a nitrogen atom in which R¹ is as defined above for R¹ prepared by the synthesis (K)) The pyrrole derivative (IV-L) can be synthesized by performing cyclization of the aminopropenitrile derivative (V-K) in the presence of a base.

The reaction between the 3-oxopropanenitrile derivative (VII-K) and the glycinemethylester derivative is performed using a solvent such as acetic acid at a temperature in a range of 0° C. to 150° C.

The cyclization reaction of the aminopropenitrile derivative (V-K) is performed using a solvent such as acetonitrile or ethylene glycol dimethyl ether in the presence of a base such as 1,8-diazabicyclo[5,4,0]-7-undecene or cesium carbonate at a temperature in a range of 0° C. to 150° C.

The thus obtained pyrrolopyrimidinone derivatives of formula (I) have an inhibitory effect of GSK-3 activity, and can be advantageously used as preventive and/or therapeutic agents which are clinically applicable GSK-3 inhibitors. Diseases that can be treated by the GSK-3 activity inhibitor include diabetes, diabetic complications, atherosclerosis, hypertension, obesity, syndrome X, Alzheimer's disease, neurodegenerative diseases (AIDS encephalophy, Huntington's disease, Parkinson's disease, or ischemic attack), manic depressive psychosis, traumatic cerebrospinal injury, alopecia, inflammatory response syndrome, cancer and immunodeficiency.

Also, the pyrrolopyrimidinone derivatives of formula (I) and its pharmaceutically acceptable salts may be formed as pharmaceutical compositions together with pharmacologically acceptable carriers and/or diluents. The compositions of the present invention may be formed as various kinds of formulations to be administered orally or parenterally. The term “parenteral” as used herein includes intravenous, subcutaneous, intramuscular, percutaneous, and rectal injection or infusion techniques.

For oral administration, examples of the formulation include tablets, pills, granules, powder, solutions, suspensions, syrups, and so on.

Here, the tablet formulations can be formed by conventional methods using a pharmaceutically acceptable carrier such as a vehicle, a binding agent, a disintegrating agent, and the like. The pills, granules and powder can also be formed by conventional methods using a vehicle or the like, like the tablets. The formulations in the form of solutions, suspensions and syrups can be prepared by general methods using glycerine esters, alcohols, water, vegetable oils, and so on. The capsule formulations can be formed by filling capsules of gelatin with granules, powder or solutions.

Among formulations for parenteral administration, intravenous, subcutaneous, and intramuscular administration can take forms of injectable formulations. For injection, the compounds of the invention may be formulated in aqueous solutions such as physiological saline or in nonaqueous solutions including organic esters such as propylene glycol, polyethylene glycol, or vegetable oils.

For transdermal administration, formulations can be used in the form of ointment or cream. Ointments can be used in combination with oils or vaselin, for example. Creams can be prepared in combination with emulsifying agents, for example.

When required, these formulations can be further provided with pharmaceutically acceptable carriers such as an isotonic, a preservative, an antiseptic, a wetting agent, a buffering agent, an emulsifying agent, a dispersing agent, or a stabilizer.

Also, such a variety of formulations can be sterilized through appropriate treatments, for example, filtration using a bacteria retaining filter or combination of disinfectants.

The amount of the pyrrolopyrimidinone derivative of formula (I) and its pharmaceutically acceptable salt that may be administered may vary depending upon the kind of a disease, administration route, symptom, age, sex, body weight, and so on of the patient. Generally, a dosage for oral administration is between 0.1 and 500 mg/day/patient. A dosage for parenteral application, including intravenous, subcutaneous, intramuscular, and percutaneous injection is between 0.1 and 100 mg/day/patient.

EXAMPLES

The present invention will now be described in more detail through the following examples. However, the present invention is not limited to these examples. In the following examples, compound numbers labeled for the respective compounds correspond to the compound numbers labeled for the compounds listed in the above tables as specific examples.

Note that, with regard to data for compounds synthesized in the following examples, the term “HPLC retention time” refers to a retention time (unit: min) associated with a particular compound in HPLC analysis performed under the following analysis condition. HPLC (High performance liquid chromatography) Analysis Condition

System: Hewlett-Packard 1100 HPLC

Column: Cadenza CD-C18 (manufactured by Imtakt Co.) 100 mm×4.6 mmφ

Solvent A:

H₂O/acetonitrile=95/5 (0.05% trifluoroacetic acid)

Solvent B:

H₂O/acetonitrile=5/95 (0.05% trifluoroacetic acid)

Flow rate: 1.0 mL/min

Gradient:

0 to 1 min Solvent B: 10%, Solvent A: 90%

1 to 14 min Solvent B: 10% →100%, Solvent A: 90% →0%

14 to 16 min Solvent B: 100%, Solvent A: 0% Calculation of the purity: Area percentage at UV absorption (254 nm)

Reference Example 1

Synthesis of (cyclopropylhydroxy-methylene)methane-1,1-dicarbonitrile

A tetrahydrofuran (150 mL) suspension of sodium hydride (11.49 g) was cooled to 0° C. To the cooled suspension was added dropwise a tetrahydrofuran (50 mL) solution of malononitrile (15.8 g) over an hour. The reaction mixture was stirred at room temperature for 1 hour and cooled to 0° C. To the reaction mixture was added dropwise over 80 minutes a tetrahydrofuran (50 mL) solution of cyclopropylcarbonyl chloride (25.0 g). The reaction mixture was stirred at room temperature for 49 hours, followed by adding water (50 mL) to the reaction solution. The solvent was distilled off under reduced pressure. To the residue were added ethyl acetate (200 mL) and hydrochloric acid (270 mL, 1 mol/L), which was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product (40.9 g) of the title compound. The NMR data of the compound is given below.

¹H-NMR(400 MHz, CDCl₃)δ(ppm): 1.10-1.22(m, 4H), 2.10-2.22(m, 1H), 4.27(s, 3H).

In a similar manner as described above, [(3-chloro(2-thienyl))hydroxymethylene]methane-1,1-dicarbonitrile was prepared from malononitrile and 3-chlorothiophene-2-carbonylchloride. The NMR data and ESI/MS data of the compound are given below.

¹H-NMR(400 MHz, CD₃OD) δ(ppm): 6.92 (d,J=5.1,1H) 7.51(d,J=5.4,1H)

ESI/MS m/e: (M⁺+H, C₈H₃ClN₂OS)

Reference Example 2

Synthesis of (cyclopropylmethoxy-methylene)methane-1,1-dicarbonitrile

A tetrahydrofuran (100 mL) suspension of sodium hydride (2.6 g) was cooled to 0° C. To the cooled suspension was added dropwise a tetrahydrofuran (60 mL) solution of crude (1-hydroxy-2-phenylmethylidene)methane-1,1-dicarbonitrile (14.5 g) over 30 minutes. The reaction mixture was stirred at room temperature for 20 minutes and cooled to 0° C. To the reaction mixture was added dropwise a tetrahydrofuran solution (40 mL) of dimethyl sulfate (13.7 g) over 1 hour. After heating for 21 hours to reflux, the reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. To the residue were added ethyl acetate (100 mL) and saturated sodium hydrogen carbonate solution (100 mL), and extraction with ethyl acetate was performed. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained crude product was purified by column chromatography on silica gel using hexane/ethyl acetate=1/3 as an eluent to obtain the title compound (6.8 g, 54%) as a light yellow solid. NMR data of the compound is given below.

¹H-NMR(400 MHz, CDCl₃)δ(ppm): 1.10-1.22(m,4H), 2.10-2.22(m,1H), 4.27(s,3H)

Reference Example 3

Synthesis of methyl 3-amino-1-{2-[(t-butoxy)carbonylamino]ethyl}-4-cyano-5-cyclopropylpyrrole-2-carboxylate

To an acetonitrile (150 mL) solution of (methoxycyclopropylmethylene)methane-1,1-dicarbonitrile (8.7 g) was added N-(2-aminoethyl) t-butyl carbaminic acid (16.3 g) and stirred at room temperature for 10 minutes. To the resultant product were added anhydrous cesium carbonate (38.5 g) and methyl bromoaccetate (11.2 mL), followed by heating for 6 hours to reflux. The reaction product was cooled to room temperature and allowed to stand. Then, the supernatant was separated by decantation and the solvent was distilled off under reduced pressure. The concentrated residue and a solid remaining after decantation were collected and ethyl acetate and water were added thereto, followed by extracting 3 times with ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After magnesium sulfate was removed by filtration, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=2/1) to obtain the title compound (17.5 g, yield 85%). The ESI/MS data of the compound are given below.

ESI/MS m/e: 349.1 (M⁺+H, C₁₇H₂₄N₄O₄)

Methyl 3-amino-1-{2-[(t-butoxy)carbonylamino}ethyl}-5-(3-chloro(2-thienyl))-4-cyanopyrrole-2-carboxylate was synthesized from [(3-chloro(2-thienyl))hydroxymethylene] methane-1,1-dicarbonitrile used as a starting material in a similar manner to that in Reference Examples 2 and 3. The ESI/MS data of the compound are given below.

ESI/MS m/e: 425.2 (M⁺+H, C₁₈H₂₁ClN₄O₄S)

Reference Example 4

Synthesis of (t-butoxy)-N-[2-(7-cyano-4-oxo-6-cyclopropyl(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)) ethyl]carboxyamide

Methyl 3-amino-1-{2-[(t-butoxy)carbonylamino]ethyl}-4-cyano-5-cyclopropylpyrrole-2-carboxylate (17.4 g) and formamidine acetate (104.1 g) were added to 2-propanol (360 mL) and heated for 45 hours to reflux. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. To the residue was added water, and the obtained solid was isolated by filtration and sufficiently washed with water. The resulting solid was recrystallized (ethanol/ethyl acetate/hexane=1/2/1) to obtain the title compound (9.8 g, yield 57%). The ESI/MS data of the compound are given below.

ESI/MS m/e: 362.1 (M⁺+H, C₁₇H₂₁N₅O₃)

(t-butoxy)-N-{2-[6-(3-chloro(2-thienyl))-7-cyano-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide was prepared from methyl-3-amino-1-{2-[(t-butoxy)carbonyl-amino]ethyl}-5-(3-chloro(2-thienyl))-4-cyanopyrrole-2-carboxylate in a similar manner to that described above. ESI/MS data of the compound are given below.

ESI/MS m/e: 420.2 (M⁺+H, C₁₈H₁₈ClN₅O₃S)

Reference Example 5

Synthesis of 3-oxo-2-(3-pyridyl) propanenitrile hydrochloride

To a toluene solution (100 mL) of 3-pyridylacetonitrile (40.86 g) was added dimethylformamidedimethylacetal (123.6 g) and the mixture was heated for 4 hours to reflux. The reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate) to obtain a brown solid. The obtained brown solid was washed with ethyl acetate, yielding 46.93 g of a colorless solid. To a tetrahydrofuran (300 mL) suspension of the reaction product (20.37 g) were added water (40 mL) and concentrated hydrochloric acid (24.50 mL) and the mixture was stirred at 50° C. for 4 hours. The reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure. The residue was dried in vacuo to obtain a crude product (30.12 g) of the title compound, which was used for the subsequent reaction without further purification. ESI/MS data of the compound are given below.

ESI/MS m/e: 147.1 (M⁺+H, C₈H₆N₂O HCl)

Reference Example 6

Synthesis of ethyl 3-{((1Z)-2-cyano-2-(3-pyridyl)vinyl)[(methoxycarbonyl)methyl]amino}propanate

To an acetic acid (30 mL) solution of ethyl 3-{[(methoxycarbonyl)methyl]amino}propanate (6.720 g) was added a crude product of 3-oxo-2-(3-pyridyl)propanenitrile (7.826 g), and the mixture was stirred at 80° C. for 2 days. The reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure. The residue was diluted with water, and sodium carbonate was added thereto for neutralization, followed by extracting the solution with ethyl acetate. The organic layer was washed with saturated brine, and dried over sodium sulfate, which was then filtered for separation. Thereafter, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=1/3), to obtain the title compound (7.521 g, yield 83%). The ESI/MS data of the compound are given below.

ESI/MS m/e: 318.2 (M⁺+H, C₁₆H₁₉N₃O₄)

Reference Example 7

Synthesis of ethyl 3-[3-amino-2-(methoxycarbonyl)-4-(3-pyridyl)pyrrolyl]propanate

To an ethylene glycol dimethyl ether (50 mL) solution of ethyl 3-{((1Z)-2-cyano-2-(3-pyridyl)vinyl)[(methoxycarbonyl)methyl]amino}propanate (6.236 g) was added 1,8-diazabicyclo [5,4,0]-7-undecene (3.590 g), and the mixture was stirred at 60° C. overnight. The reaction solution was cooled to room temperature and neutralized with acetic acid, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=1/5), to obtain the title compound (4.380 g, yield 70%). The NMR data and ESI/MS data of the compound are given below.

¹H-NMR(400 MHz, DMSO-d₆) δ(ppm): 1.10-1.18(m,3H), 2.74(t,J=6.82, 2H), 3.77(s,3H), 3.99-4.07(m,2H), 4.38(t,J=6.84, 2H), 7.46(s,1H), 7.85(dd,J=5.74,J=7.94,1H), 8.36(d,J=8.08, 1H), 8.60(d,J=5.40, 1H), 8.84(s,1H).

ESI/MS m/e: 318.2(M⁺+H, C₁₆H₁₉N₃O₄)

Reference Example 8

Synthesis of (cyclopropylhydroxy-methylene)methane-1-(3-pyridyl)-1-carbonitrile

To a 500 mL branched flask was added 13.0 g of 3-pyridinacetonitrile (110 mmol) and 150 mL of tetrahydrofuran, and 44 mL of ⁿBuLi (2.6 M solution) (114 mmol) was added dropwise thereto using a syringe with stirring at 0° C., followed by stirring at 0° C. for 30 minutes and at 40° C. for 30 minutes. While the reaction product was cooled at 0° C. with stirring, a tetrahydrofuran solution (30 mL) of 10.45 g of cyclopropanecarbonyl chloride (100 mmol) was added dropwise, and stirred at room temperature for 1 hour, followed by adding to the reaction solution 300 mL of a saturated ammonium chloride solution and separated. The aqueous layer was extracted with 100 mL of ethyl acetate. The organic layer was washed twice with 300 mL of saturated brine. The organic layer was dehydrated and dried over magnesium sulfate, filtered and concentrated to obtain 18.25 g of concentrated residue. To the concentrated residue was added 30 mL of acetonitrile and an insoluble portion was filtered off, followed by washing with 20 mL of acetonitrile to obtain a crude product of the title compound (5.17 g, 28%). The NMR data and ESI/MS data of the compound are given below.

¹H-NMR(400 MHz, DMSO-d₆)δ(ppm): 0.64(m,4H), 2.24(m,1H) 2.50(brds,1H), 7.70(dd,J=5.4 Hz,J=8.6 Hz,1H), 8.11(d,J=5.4 Hz,1H), 8.21(d,J=8.6 Hz,1H), 9.12(brds,1H).

ESI/MS m/e: 187.1(M⁺+H, C₁₁H₁₀N₂O)

Reference Example 9

Synthesis of (cyclopropyl-p-toluene-sulfonyloxymethylene)methane-1-(3-pyridyl)-1-carbonitrile

A 200 mL branched flask were charged with 4.51 g of (cyclopropylhydroxymethylene)methane-1-(3-pyridyl)-1-carbonitrile (24.3 mmol) and 9.14 g of p-toluene sulfonic anhydride (28 mmol), and 100 mL of dichloromethane was added thereto, followed by adding 4.8 mL of triethylamine (34.5 mmol) dropwise with stirring the reaction mixture at room temperature, and stirring at room temperature for 2 hours. After the completion of the reaction, 50 mL of water was added to the reaction solution and separated. The aqueous layer was extracted with 20 mL of dichloromethane. The organic layer was washed once with 50 mL of saturated sodium hydrogen carbonate solution and twice with 50 mL of water. The organic layer was dehydrated and dried over magnesium sulfate, filtered and concentrated to obtain a crude product (8.47 g, 100%) of the title compound. The NMR data and ESI/MS data of the compound are given below.

¹H-NMR(270 MHz, CDCl₃)δ(ppm): 1.10-1.32(m,4H), 2.40(s,3H) 2.15-2.42(m,1H), 7.05(m,3H), 7.40(m,2H), 7.60(m,1H), 8.40(m,2H).

ESI/MS m/e: 341.0(M⁺+H, C₁₈H₁₆N₂O₃S)

Reference Example 10

Synthesis of ethyl 3-amino-4-(3-pyridyl)-5-cyclopropylpyrrole-2-carboxylate

A 200 mL branched flask was charged with 7.764 g of (cyclopropyl-p-toluenesulfonyloxymethylene)methane-1-(3-pyridyl)-1-carbonitrile (22.8 mmol), and 70 mL of ethanol and 35 mL of tetrahydrofuran were added thereto, followed by adding 5.08 g of diethylaminomalonate hydrochloric acid (24 mmol) with stirring the reaction mixture at 0° C., and stirring at 0° C. for 1 hour. Subsequently, 35 mL of an ethanol solution of sodium ethoxide (5.43 g, 80 mmol) was added dropwise to the reaction solution and stirred at 0° C. for 1 hour. After the completion of the reaction, the solvent was concentrated under reduced pressure and concentrated. To the residue were added 150 mL of water and ethyl 100 mL of acetate for extraction. The aqueous layer was extracted with 50 mL of ethyl acetate. The organic layer was washed once with 100 mL of water and three times with 50 mL of saturated brine solution. The organic layer was dehydrated and dried over magnesium sulfate, filtered and concentrated to obtain 3.90 g of a crude product, which was then purified by column chromatography (silica gel 100 g; using 4:1 to 0:1 hexane/ethyl acetate as an eluent) to obtain the title compound (1.074 g, yield 17%). The NMR data and ESI/MS data of the compound are given below.

¹H-NMR (270 MHz, CDCl₃) δ(ppm): 0.60-0.95(m,4H) 1.30(m,1H), 1.36(t,J=7.0 Hz,3H), 4.15(q,J=7.0 Hz,2H), 4.35(brds,2H), 7.15(m,1H), 7.75(m,1H), 8.50(m,1H), 8.75(s,1H).

ESI/MS m/e: 272.1(M⁺+H, C₁₅H₁₇N₃O₂)

Reference Example 11

Synthesis of N-{2-[4-chloro-6-(3-chloro(2-thienyl))-7-iodopyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-2,2,2-trifluoroacetamide

A 3.0 mL phosphorus oxychloride solution of N-{2-[6-(3-chloro(2-thienyl))-7-iodo-4-oxo(3-hydropyrrolo [3,2-d]pyrimidin-5-yl)]ethyl}-2,2,2-trifluoroacetamide (333 mg) was stirred at 110° C. for 2 hours. The reaction mixture was cooled to room temperature, and excess phosphorus oxychloride was distilled off under reduced pressure. The residue was dried in vacuo to obtain a crude product of the title compound, which was used for the subsequent reaction without further purification. The ESI/MS data of the compound are given below.

ESI/MS m/e: 535.2(M⁺+H, C₁₄H₈Cl₂F₃IN₄OS)

Reference Example 12

Synthesis of N-{2-[7-bromo-4-chloro-6-(3-chloro(2-thienyl))pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-2,2,2-trifluoroacetamide

A crude product of the title compound was prepared from N-{2-[7-bromo-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo [3,2-d]pyrimidin-5-yl)]ethyl}-2,2,2-trifluoroacetamide in a similar manner to that described in Reference Example 11. The ESI/MS data of the compound are given below.

ESI/MS m/e: 489.0(M⁺+H, C₁₄H₈BrCl₂F₃N₄OS)

Reference Example 13

Synthesis of N-{2-[4,7-dichloro-6-(3-chloro(2-thienyl))pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-2,2,2-trifluoroacetamide

A crude product of the title compound was prepared from N-{2-[7-chloro-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}-2,2,2-trifluoroacetamide in a similar manner to that described in Reference Example 11. The ESI/MS data of the compound are given below.

ESI/MS m/e: 443.4(M⁺+H, C₁₄H₈Cl₃F₃N₄OS)

Reference Example 14

Synthesis of N-(2-{7-[(1E)-1-aza-2-(dimethylamino)vinyl]-4-chloro-6-(3-chloro(2-thienyl)) pyrrolo[3,2-d]pyrimidin-5-yl}ethyl)(4-fluorophenyl) carboxyamide

N-(6-(3-chloro(2-thienyl))-5-{2-[(4-fluorophenyl) carbonylamino]ethyl}-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-7-yl))-2,2,2-trifluoroacetamide (1.09 g) was used to obtain a crude product (0.87 g) of the title compound in the same way as Reference Example 11. NMR data and ESI/MS data of the compound are given below.

¹H-NMR(400 MHz, DMSO-d₆)δ(ppm): 2.81(brs,1H), 2.97(brs,1H), 3.28(s,2H), 3.37-3.45(m,2H), 7.17-7.27(m,3H), 7.55-7.68(m,2H), 7.86(d,J=5.4, 1H), 8.31-8.38(m,1H), 8.61(s,1H), 8.75(s,1H).

ESI/MS m/e: 505.4(M⁺+H, C₂₂H₁₉Cl₂FN₆OS)

Example 1

Synthesis of 5-{2-[(t-butoxy)carbonylamino]ethyl}-6-{3-chloro(2-thienyl)}-4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-7-carboxyamide (Compound No: 950)

(t-butoxy)-N-{2-[6-{3-chloro(2-thienyl)}-7-cyano-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide (3.0 g) was dissolved in ethanol (100 mL), and a 5M aqueous sodium hydroxide solution (20 mL) was added thereto. A 30% hydrogen peroxide solution (30 mL) was added to the reaction mixture over 20 minutes with stirring. After stirring at 45 to 50° C. for 24 hours, 30% hydrogen peroxide solution (20 mL) was added to the reaction solution, stirred at 45 to 50° C. for 24 hours, concentrated and neutralized with 1 M hydrochloric acid, to obtain a white precipitate. The precipitate was filtered, washed, and dried under reduced pressure to obtain the title compound (2.68 g, yield 86%). The HPLC retention time, NMR data and ESI/MS data of the compound are given below.

HPLC retention time=7.2 (min)

¹H-NMR (270 MHz, DMSO-d₆)δ(ppm): 1.26(s,9H), 3.2-3.5(m,2H), 3.8-4.0(m,1H), 4.4-4.6(m,2H), 6.5-6.6(m,1H), 7.17(d,1H,J=4.6 Hz), 7.2-7.3(m,1H), 7.91(d,1H,J=5.4 Hz),8.0-8.1(m,1H), 12.4-12.5(m,1H).

ESI/MS m/e: 438.3(M⁺+H, C₁₈H₂₀ClN₅O₄S

Example 2

Synthesis of 5-{2-[(t-butoxy)carbonylamino]ethyl}-6-cyclopropyl-4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-7-carboxyamide (Compound No: 898)

The title compound was prepared from (t-butoxy)-N-{2-[6-cyclopropyl-7-cyano-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide in a similar manner to that described in Example 1. The ESI/MS data of the compound are given below.

ESI/MS:m/e 362.1(M⁺+H, C₁₇H₂₃N₅O₄)

Example 3

Synthesis of N-[2-[7-amino-6-(3-chloro (2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)] ethyl} (t-butoxy)carboxyamide (Compound No: 959)

5-{2-[(t-butoxy)carbonylamino]ethyl}-6-(3-chloro(2-thienyl))₄-oxo-3-hydropyrrolo[3,2-d]pyrimidine-7-carboxyamide (110 mg) was suspended in a 1 M aqueous sodium hydroxide solution (7.5 mL), and benzyltrimethylammonium tribromide (135 mg) was added thereto and the mixture was stirred for 1.5 hours. 1 M hydrochloric acid was added to the reaction mixture to acidify the reaction system, and then washed with ethyl acetate. The aqueous layer was made alkaline with sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography on silica gel (15 g) using 1:1 to 0:1 hexane:ethyl acetate as an eluent to obtain the title compound (72 mg, yield 70%). The NMR data and ESI/MS data of the compound are given below.

HPLC retention time=6.4 (min)

¹H-NMR (270 MHz,CDCl₃)δ(ppm): 1.32(s,9H), 3.3-3.5(m,2H), 4.3-4.5(m,2H), 4.9-5.0(m,1H), 7.11(d,1H,J=5.4 Hz), 7.54(d,1H,J=5.4 Hz), 7.79(brs,1H), 10.0-10.1(m,1H).

ESI/MS m/e: 410.3(M⁺+H, C₁₇H₂₀ClN₅O₃S)

Example 4

Synthesis of N-{2-[7-amino-6-cyclopropyl-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}(t-butoxy)carboxyamide (Compound No: 903)

The title compound was prepared from 5-{2-[(t-butoxy)carbonylamino]ethyl}-6-cyclopropyl-4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-7-carboxyamide in a similar manner to that described in Example 3. The NMR data and ESI/MS data of the compound are given below.

¹H-NMR(270 MHz, CDCl₃)δ(ppm): 1.34(s,9H), 0.8-1.2(m,5H), 3.4(brs,2H), 3.5-3.6(m,3H), 4.5-4.6(m,2H), 5.6(brs,1H), 7.8(brs,1H)

ESI/MS m/e: 334.1(M⁺+H, C₁₆H₂₃N₅O₃)

Example 5

Synthesis of (t-butoxy)-N-{2-[7-bromo-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide (Compound No: 945)

To 30 mg of N-{2-[7-amino-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}(t-butoxy)carboxyamide, 1 ml of bromoform was added, followed by adding 50 μl of isoamyl nitrite. After stirring at 70° C. for 4 hours, saturated brine was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated, followed by subjecting to thin layer chromatography on silica gel using ethyl acetate as a developing solvent to obtain the title compound (15 mg, yield 43%). The HPLC retention time, NMR data and ESI/MS data of the compound are given below.

HPLC retention time=9.5 (min)

¹H-NMR(270 MHz,CDCl₃)δ(ppm): 1.31(s,9H), 3.3-3.5(m,2H) 4.2-4.3(m,1H), 4.5-4.7(m,1H), 4.7-4.9(m,1H), 7.13(d,1H,J=5.7 Hz), 7.60(d,1H,J=5.4 Hz), 7.94(d,1H,J=3.0 Hz).

ESI/MS m/e 475.2(M⁺+H, C₁₇H₁₈BrClN₄O₃S)

Example 6

Synthesis of (t-butoxy)-N-{2-[7-bromo-6-cyclopropyl-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)] ethyl}carboxyamide (Compound No: 2511)

The title compound was prepared from N-{2-[7-amino-6-cyclopropyl-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}(t-butoxy)carboxyamide in a similar manner to that described in Example 5. The HPLC retention time, NMR data and ESI/MS data of the compound are given below.

HPLC retention time=8.5 (min)

1H-NMR(270 MHz, CDCl₃)δ(ppm): 1.31(s,9H), 1.1-1.3(m,5H), 3.5-3.9(m,3H), 4.5-4.9(m,2H), 5.1-5.3(brs,1H), 7.9(s,1H)

ESI/MS m/e: 397.1(M⁺+H, C₁₆H₂₁BrN₄O₂S)

Example 7

Synthesis of (t-butoxy)-N-{2-[6-(3-chloro(2-thienyl))-7-iodo-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide (Compound No: 946)

To 1 g of N-{2-[7-amino-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}(t-butoxy)carboxyamide, 7 mL of diiodomethane was added, followed by adding 822 μl of isoamyl nitrite. After stirring at 70° C. for 4 hours, saturated brine was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated, followed by subjecting to chromatography on silica gel (using 5:1 to 0:1 hexane/ethyl acetate as an eluent), to yield the title compound (694 g, yield: 55%). NMR data and ESI/MS data of the compound are given below.

HPLC retention time=9.6 (min)

¹H-NMR(270 MHz,CDCl₃)δ(ppm):1.32(s,9H), 3.3-3.5(m,2H), 4.2-4.35(m,1H), 4.6-4.75(m,1H), 4.8-5.0(m,1H), 7.14(d,1H,J=5.4 Hz), 7.59(d,1H,J=5.7 Hz), 7.95-8.05(m,1H).

ESI/MS m/e 521.3(M⁺+H, C₁₇H₁₈ClIN₄O₃S

Example 8

Synthesis of (t-butoxy-N-{2-[7-iodo-6-cyclopropyl]-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)}Ethyl)carboxyamide (Compound No: 896)

The title compound was prepared from N-{2-[7-amino-6-cyclopropyl-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}(t-butoxy)carboxyamide in a similar manner to that described in Example 7. The HPLC retention time, NMR data and ESI/MS data of the compound are given below.

HPLC retention time=8.7 (min)

¹H-NMR(270 MHz, CDCl₃)δ(ppm): 1.31(s,9H), 1.0-1.3(m,5H), 3.5-3.8(m,3H), 4.7-4.9(m,2H), 5.2-5.3(brs,1H), 7.9(s,1H)

ESI/MS m/e: 445.4(M⁺+H, C₁₆H₂₁IN₄O₃)

Example 9

Synthesis of (t-butoxy)-N-{2-[7-chloro-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide (Compound No: 944)

To 20 mg of N-{2-[7-amino-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}(t-butoxy)carboxyamide, 2 ml of carbon tetrachloride was added, followed by adding 34 μl of isoamyl nitrite. After refluxing for 40 hours, saturated brine was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated, followed by subjecting to thin layer chromatography on silica gel (using ethyl acetate as a developing solvent) to obtain the title compound (5 mg, yield: 24%). The HPLC retention time, NMR data and ESI/MS data of the compound are given below.

HPLC retention time=9.4 (min)

¹H-NMR(270 MHz, CDCl₃)δ(ppm): 1.32(s,9H), 3.3-3.5(m,2H), 4.15-4.4(m,1H), 4.6-4.75(m,1H), 4.8-4.95(m,1H), 7.13(d,1H,J=5.4 Hz), 7.60(d,1H,J=5.4 Hz), 7.98(brs,1H).

ESI/MS m/e 429.4(M⁺+H, C₁₇H₁₈Cl₂N₄O₃S)

Example 10

Synthesis of (t-butoxy)-N-{2-[6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide (Compound No. 943)

To 15 mg of N-{2-[7-amino-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}(t-butoxy)carboxyamide, 2 mL of tetrahydrofuran was added, followed by adding 50 μl of isoamyl nitrite. After stirring at 50° C. for 3 hours, saturated brine was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated, followed by subjecting to thin layer chromatography on silica gel (developing solvent: ethyl acetate) to obtain the title compound (8 mg, yield 55%). The NMR data and ESI/MS data of the compound are given below.

HPLC retention time=8.4 (min)

¹H-NMR(270 MHz,CDCl₃) δ(ppm): 1.31(s,9H), 3.3-3.5(m,2H) 4.4-4.6(m,2H), 5.01(brs,1H), 6.66(s,1H), 7.07(d,1H, J=5.4 Hz), 7.49(d,1H, J=5.1 Hz), 7.93(brs, 1H), 11.2-11.3(m,1H).

ESI/MS m/e 395.2(M⁺+H, C₁₇H₁₉ClN₄O₃S)

Example 11

Synthesis of 5-(2-aminoethyl)-6-(3-chloro (2-thienyl))-7-iodo-3-hydropyrrolo[3,2-d]pyrimidin-4-one hydrochloride (Compound No. 206)

(t-butoxy)-N-{2-[6-(3-chloro(2-thienyl))-7-iodo-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide (331 mg) was dissolved in a mixed solution of methanol (0.5 mL) and 1,4-dioxane (5.0 mL), and hydrochloric acid/1,4-dioxane solution (4 mol/L, 0.64 mL) was added and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. The residue was dried under reduced pressure to obtain the title compound (334 mg in a quantitative yield). The ESI/MS data of the compound are given below.

ESI/MS m/e: 421.2 (M⁺+H, C₁₂H₁₀ClN₄OS HCl)

Example 12

Synthesis of 5-(2-aminoethyl)-7-bromo-6-(3-chloro(2-thienyl))-3-hydropyrrolo[3,2-d]pyrimidin-4-one hydrochloride (Compound No. 205)

The title compound was prepared from (t-butoxy)-N-{2-[7-bromo-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo [3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide in a similar manner to that described in Example 11. The ESI/MS data of the compound are given below.

ESI/MS m/e: 375.0(M⁺+H, C₁₂H₁₀BrClN₄OS HCl)

Example 13

Synthesis of 5-(2-aminoethyl)-7-chloro-6-(3-chloro(2-thienyl))-3-hydropyrrolo[3,2-d]pyrimidin-4-one hydrochloride (Compound No. 204)

The title compound was prepared from (t-butoxy)-N-{2-[7-chloro-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide in a similar manner to that described in Example 11. The ESI/MS data of the compound are given below.

ESI/MS m/e: 329.4(M⁺+H, C₁₂H₁₀Cl₂N₄OS HCl)

Example 14

Synthesis of N-{2-[6-(3-chloro(2-thienyl))-7-iodo-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}-2,2,2-trifluoroacetamide (Compound No. 320)

To a tetrahydrofuran (5.0 mL) solution of 5-(2-aminoethyl)-6-(3-chloro(2-thienyl))-7-iodo-3-hydropyrrolo[3,2-d]pyrimidin-4-one hydrochloride (259 mg) was added trifluoroacetic anhydride (595 mg), and triethylamine (1.2 mL) was added slowly dropwise. The reaction mixture was stirred at room temperature for 2 hours, and methanol was added to stop the reaction. The solvent was distilled off under reduced pressure. To the residue were added water and ethyl acetate, which was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After anhydrous magnesium sulfate was filtered off, the solvent was distilled off under reduced pressure. The residue was dried under reduced to obtain a crude product (365 mg) of the title compound. The HPLC retention time, NMR data and ESI/MS data of the compound are given below.

HPLC retention time=9.1(min)

¹H-NMR(400 MHz, DMSO-d₆)δ(ppm): 3.45(m,2H), 4.16(m,1H) 4.61(m,1H), 7.30(m,1H), 7.93(m,1H), 8.02(m,1H), 9.37 (m,1H), 12.29 (brs,1H).

ESI/MS m/e: 517.2(M⁺+H, C₁₄H₉ClF₃₁N₄O₂S)

Example 15

Synthesis of N-{2-[7-bromo-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}-2,2,2-trifluoroacetamide (Compound No. 319)

The title compound was prepared from 5-(2-aminoethyl)-7-bromo-6-(3-chloro(2-thienyl))-3-hydropyrrolo[3,2-d]pyrimidin-4-one hydrochloride in a similar manner to that described in Example 14. The ESI/MS data of the compound are given below.

ESI/MS m/e: 471.1(M⁺+H, C₁₄H₉BrClF₃N₄O₂S)

Example 16

Synthesis of N-{2-[7-chloro-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}-2,2,2-trifluoroacetamide (Compound No. 318)

The title compound was prepared from 5-(2-aminoethyl)-7-chloro-6-(3-chloro(2-thienyl))-3-hydropyrrolo[3,2-d]pyrimidin-4-one hydrochloride in a similar manner to that described in Example 14. The ESI/MS data of the compound are given below.

ESI/MS m/e: 425.4(M⁺+H, C₁₄H₉Cl₂F₃N₄O₂S)

Example 17

Synthesis of N-{2-[6-(3-chloro(2-thienyl))-7-iodo-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}(4-fluorophenyl)carboxyamide (Compound No. 344)

To an N,N-dimethylacetamide (2.0 mL) solution of 5-(2-aminoethyl)-6-(3-chloro(2-thienyl))-7-iodo-3-hydropyrrolo[3,2-d]pyrimidin-4-one hydrochloride (33 mg) was added 4-fluorobenzoylchloride (23 mg), and the mixture was stirred at room temperature for a short time, followed by adding triethylamine (0.2 mL) and stirring at room temperature for 2 hours. To the reaction solution was added water (0.2 mL), and the solution was stirred again at room temperature overnight. The solvent was distilled off under reduced pressure, and the residue was purified by fraction HPLC to obtain the title compound (22 mg, yield 55%). The HPLC retention time, NMR data and ESI/MS data of the compound are given below.

HPLC retention time=9.1 (min)

¹H-NMR(400 MHz, DMSO-d₆) δ(ppm): 3.52(m,2H), 4.24(m,1H), 4.63(m,1H), 7.19-7.26(m,3H), 7.70-7.74(m,2H), 7.88-7.92(m,2H), 8.45(m,1H), 12.24(brs,1H).

ESI/MS m/e: 543.4(M⁺+H, C₁₉H₁₃ClFIN₄O₂S)

Example 18

Synthesis of 6-(3-chloro(2-thienyl))-7-iodo-5-[2-(quinazolin-4-ylamino)ethyl]-3-hydropyrrolo [3,2-d]pyrimidin-4-one (Compound No. 81)

To an N,N-dimethylacetamide (2.0 mL) solution of 5-(2-aminoethyl)-6-(3-chloro(2-thienyl))-7-iodo-3-hydropyrrolo[3,2-d]pyrimidin-4-one hydrochloride (36 mg) and 4-chloroquinazoline (10 mg), was added triethylamine (16 mg) and the mixture was stirred at 70° C. for 2 hours. Triethylamine (32 mg) was further added to the reaction mixture and stirred at 70° C. for 2 hours. The reaction mixture was cooled to room temperature and purified by fraction HPLC to obtain the title compound (21 mg, yield 49%). The HPLC retention time, NMR data and ESI/MS data of the compound are given below.

HPLC retention time: 6.9 (min)

¹H-NMR(400 MHz, DMSO-d₆)δ(ppm): 3.95(m,2H), 4.48(m,1H) 4.87(m,1H), 7.12(m,1H), 7.71-7.82(m,3H), 7.87(brs,1H), 8.00(t,J=7.7,1H), 8.18(d,J=8.3,1H), 8.60(s,1H), 9.91(brs,1H), 12.24(brs,1H). ESI/MS m/e: 549.4(M⁺+H, C₂₀H₁₄ClIN₆OS)

Example 19

Synthesis of N-(5-{2-[(t-butoxy)carbonylamino] ethyl}-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-7-yl))-2,2,2-trifluoroacetamide (Compound No. 962)

To a tetrahydrofuran solution (39 mL) of N-{2-[7-amino-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo [3,2-d]pyrimidin-5-yl)]ethyl}(t-butoxy)carboxyamide (1.60 g) was added triethylamine (2.7 mL), and cooled to 0° C., followed by adding trifluoroacetic anhydride (1.35 mL) slowly dropwise. The reaction mixture was stirred at room temperature for 1 hour, and saturated brine was added dropwise to stop the reaction. Ethyl acetate was added to the reaction solution for extraction. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was distilled off under reduced pressure to obtain the title compound (1.97 g, a quantitative yield) as a light yellow solid. The HPLC retention time, NMR data and ESI/MS data of the compound are given below.

HPLC retention time=8.7 (min)

¹H-NMR(400 MHz, DMSO-d₆)δ(ppm): 1.26(s,9H), 3.13-3.26(m,2H), 4.11(brs,1H), 4.49(brs,1H), 6.60-6.73(m,1H), 7.23(d,J=5.4,1H), 7.88(s,1H), 7.95(d,J=5.4,1H), 10.86(s,1H), 12.21(brs,1H).

ESI/MS m/e: 506.4(M⁺+H, C₁₉H₁₉ClF₃N₅O₄S)

Example 20

Synthesis of N-[5-(2-aminoethyl)-6-(3-chloro (2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-7-yl)]-2,2,2-trifluoroacetamide hydrochloride (Compound No. 207)

A methanol solution (13 mL) of N-(5-{2-[(t-butoxy) carbonylamino]ethyl}-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-7-yl))-2,2,2-trifluoroacetamide (1.97 g) was cooled to 0° C. and added was 4 mol/L hydrochloric acid/1,4-dioxane solution (26 mL), followed by stirring at room temperature for 4 hours. The solvent was distilled off under reduced pressure, yielding a crude product (1.73 g) of the title compound. The ESI/MS data of the compound are given below.

ESI/MS m/e: 406.3(M⁺+H, C₁₄H₁₁F₃N₅O₂S.HCl)

Example 21

Synthesis of N-(6-(3-chloro(2-thienyl))-5-{2-[(4-fluorophenyl)carbonylamino]ethyl}-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-7-yl))-2,2,2-trifluoroacetamide (Compound No. 345)

N-[5-(2-aminoethyl)-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-7-yl)]-2,2,2-trifluoro-acetamide crude product (1.73 g) in pyridine (39 mL) was cooled to 0° C., and 4-fluorobenzoylchloride (0.92 mL) was added thereto, followed by stirring at room temperature for 1 hour. To the reaction solution was added water (40 mL), stirred at room temperature for 1 hour, and to stop the reaction. Brine was added until the reaction solution was saturated, and extraction with ethyl acetate was performed. The organic layer was washed with a mixed solution of saturated brine and 1 mol/L of hydrochloric acid (9:1), dried over anhydrous sodium sulfate and filtered. The solvent was distilled off under reduced pressure and purified by column chromatography on silica gel using 1/2 hexane/ethyl acetate and then using ethyl acetate only as eluents to obtain the title compound (1.60 g, 78% yield for 2 steps). The HPLC retention time, NMR data and ESI/MS data of the compound are given below.

HPLC retention time=8.3 (min)

¹H-NMR(400 MHz, DMSO-d₆)δ(PPM): 3.49-3.58(m,2H) 4.34(brs,1H), 4.66(brs,₁₁H), 7.16(d,J=5.4,1H), 7.19(t,J=7.1, 2H), 7.65-7.75(m,2H), 7.83(d,J=5.4,1H), 7.88(s,1H), 8.40-8.50(m,1H), 10.85(s,1H), 12.25(brs,1H).

ESI/MS m/e: 528.4 (M⁺+H, C₂₁H₁₄ClF₄N₅O₃S)

Example 22

Synthesis of (t-butoxy)-N-{2-[6-(3-chloro (2-thienyl))-4-oxo-7-(phenylcarbonylamino)(3-hydropyrrolo [3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide (Compound No. 965)

To a tetrahydrofuran solution (10 mL) of N-{2-[7-amino-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}(t-butoxy)carboxyamide (0.41 g) was added triethylamine (0.69 mL), and the reaction mixture was cooled to 0° C. and benzoylchloride (0.29 mL) was added slowly dropwise. The reaction mixture was stirred at room temperature for 1 hour, and an aqueous sodium hydroxide solution (2 mol/L, 2.0 mL) was added dropwise and stirred for 18 hours to stop the reaction. Hydrochloric acid (1 mol/L, 4.0 mL) was added to the reaction solution for neutralization, brine was added thereto until the reaction solution was saturated, and extraction with ethyl acetate was performed. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was distilled off under reduced pressure, and purified by column chromatography was performed on silica gel using ethyl acetate only to obtain the title compound (0.51 g, a quantitative yield). The ESI/MS data of the compound are given below.

ESI/MS m/e: 514.4(M⁺+H, C₂₄H₂₄ClN₅O₄S)

Example 23

Synthesis of N-[5-(2-aminoethyl)-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-7-yl)]benzamide hydrochloride (Compound No. 208)

To a methanol solution (3.3 mL) of (t-butoxy)-N-{2-[6-(3-chloro(2-thienyl))-4-oxo-7-(phenylcarbonylamino)(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide (0.51 g) was added 4 mol/L hydrochloric acid/1,4-dioxane solution (6.6 mL) and the mixture was stirred at room temperature for 5 hours. The solvent was distilled off under reduced pressure, yielding a crude product (0.47 g) of the title compound. The ESI/MS data of the compound are given below.

ESI/MS m/e: 414.3 (M⁺+H, C₁₉H₁₆ClN₅O₂.HCl)

Example 24

Synthesis of N-{2-[6-(3-chloro(2-thienyl))-4-oxo-7-(phenylcarbonylamino)(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}(4-fluorophenyl)carboxyamide (Compound No. 346)

To a dimethylacetamide solution (1.0 mL) of N-[5-(aminoethyl)-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-7-yl)]benzamide (45 mg), were added 4-fluorobenzoylchloride (23.6 μL) and triethylamine (55 μL) and the mixture was stirred at room temperature for 1 hour. 2 mol/L of an aqueous sodium hydroxide solution (1.0 mL) was added dropwise, and the solution was stirred for 1 hour and stopped the reaction. 1 mol/L of hydrochloric acid (2.0 mL) was added to the reaction solution for neutralization, brine was added thereto until the reaction solution was saturated, and extraction with ethyl acetate was performed. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was distilled off under reduced pressure, and purified by fraction HPLC to obtain the title compound (25.5 mg, yield 48%). The HPLC retention time, NMR data and ESI/MS data of the compound are given below.

HPLC retention time=8.2 (min)

¹H-NMR(400 MHz, DMSO-d₆) δ(ppm): 3.50-3.70(m,2H), 4.35(brs,1H), 4.68(brs,1H), 7.12(d,J=5.4, 1H), 7.22(t,J=8.8, 2H), 7.44(t,J=7.3, 2H), 7.47-7.56(m,1H), 7.69-7.78(m,3H), 7.84(d,J=7.6, 2H), 7.89(s,1H), 8.47(t,J=5.4,1H), 9.72(s,1H), 12.22(brs,1H).

ESI/MS m/e: 536.4(M⁺+H, C₂₆H₁₉ClFN₅O₃S)

Example 25

Synthesis of N-{6-(3-chloro(2-thienyl))-4-oxo-5-[2-(quinazolin-4-ylamino)ethyl](3-hydropyrrolo[3,2-d]pyrimidin-7-yl)}benzamide (Compound No. 82)

N-[5-(aminoethyl)-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-7-yl)]benzamide (45 mg) and 4-chloroquinazoline (16.5 mg) were dissolved in dimethylacetamide (2.9 mL), and triethylamine (27.7 μL) was added thereto and the mixture was stirred at 70° C. for 3 hours. Triethylamine (13.9 μL) was further added to the reaction mixture and the solution was stirred at 70° C. for 5 hours. The reaction solution was cooled to room temperature and purified by fraction HPLC, to obtain the title compound (44.3 mg, 82%). The HPLC retention time, NMR data and ESI/MS data of the compound are given below.

HPLC retention time=6.4 (min)

¹H-NMR(400 MHz, DMSO-d₆)δ(ppm): 3.95-4.05(m,2H), 4.52(brs,1H), 5.00(brs,1H), 7.05(d,J=5.4,1H), 7.43(t,J=7.6, 2H), 7.52(t,J=7.3,1H), 7.65(d,J=5.4, 1H), 7.70-7.85(m,5H), 8.02(t,J=7.8, 1H), 8.23(d,J=8.5, 1H), 8.61(s,1H), 9.66(s,1H), 10.17(m,1H), 12.10(brs,1H).

ESI/MS m/e: 542.4(M⁺+H, C₂₇H₂₀ClN₇O₂S)

Example 26

Synthesis of (t-butoxy)-N-[2-[6-(3-chloro (2-thienyl))-4-oxo-7-vinyl(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide (Compound No. 966)

A nitrogen flushed flask was charged with a 0.5 M zinc chloride/tetrahydrofuran solution, and 1.0 mL of a 1.0 M vinyl magnesium bromide/tetrahydrofuran solution was added thereto with stirring, the mixture solution was stirred for 30 minutes, to obtain a suspension which was used in a subsequent reaction. To a round-bottom flask, were transferred 26 mg of (t-butoxy)-N-{2-[6-(3-chloro(2-thienyl))-4-oxo-7-iodo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide and 12 mg of tetrakistriphenylphosphine palladium (0), followed by flushing with nitrogen and adding 2 mL dry tetrahydrofuran thereto. 600 μl of the suspension was added to the reaction mixture and the mixture was stirred at 50° C. for 8 hours, and saturated brine was added thereto and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The obtained crude product was subjected to chromatography on silica gel (eluent: 5:1 to 0:1 hexane:ethyl acetate), to obtain the title compound (5.5 mg, yield 26%). The HPLC retention time and ESI/MS data of the compound are given below.

HPLC retention time=9.6 (min)

EMS/MS m/e 421.2(M⁺+H, C₁₉H₂₁ClN₄O₃S)

Example 27

Synthesis of (t-butoxy)-N-{2-[6-(3-chloro(2-thienyl))-7-(3-hydroxy-1-prop-1-ynyl)-4-oxo(3-hydropyrrolo [3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide (Compound No. 971)

A round-bottom flask was charged with 26 mg of (t-butoxy)-N-{2-[6-(3-chloro(2-thienyl))-4-oxo-7-iodo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide, 12 mg of tetrakistriphenylphosphine palladium, 3.8 mg of copper (I) iodide and 15 μl of propargyl alcohol, followed by flushing with nitrogen, and 1 mL of dry tetrahydrofuran and 209 μl of triethylamine were added thereto. The reaction mixture was stirred at 50° C. for 5 hours, and saturated brine was added thereto and extracted with ethyl acetate. The organic layer was concentrated and subjected to column chromatography on silica gel, (developing solvent: 10 mL of toluene to 8 mL of ethyl acetate:methanol=2:1). A portion eluted by ethyl acetate/methanol was concentrated and subjected to fraction HPLC to obtain the title compound. The HPLC retention time and ESI/MS data of the compound are given below.

HPLC retention time=9.0 (min)

EMS/MS m/e 448.9(M+H⁺, C₂₀H₂₁ClN₄O₄S)

Example 28

Synthesis of N-{2-[7-benzo[d]furan-2-yl-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}(t-butoxy)carboxyamide (Compound No. 1000)

A round-bottom flask was charged with 26 mg of (t-butoxy)-N-{2-[6-(3-chloro(2-thienyl))-4-oxo-7-iodo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide, 2.2 mg of palladium acetate, triphenylphosphine, 26 mg of sodium carbonate and 16.2 mg of 2-benzofuranyl boric acid and flushed with nitrogen. 1 mL of a solution containing dimethylformamide and water mixed in a ratio of 2:1 was added to the reaction mixture and the mixture was stirred at 80° C. for 24 hours, and saturated brine was added thereto and extracted with ethyl acetate. The organic layer was concentrated and subjected to chromatography on silica gel, (developing solvent: 10 mL of toluene to 8 mL of ethyl acetate/methanol=2:1). A portion eluted by ethyl acetate/methanol was concentrated and subjected to fraction HPLC to obtain the title compound. The HPLC retention time and ESI/MS data of the compound are given below.

HPLC retention time=11.6 (min)

EMS/MS m/e 511.3(M+H⁺, C₂₅H₂₃ClN₄O₄S)

Example 29

Synthesis of N-{2-[6-(3-chloro-thiophen-2-yl)-7-iodo-4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-t-butylacetylamide (Compound No. 625)<

To an N,N-dimethylacetamide solution (5.0 mL) of 5-(2-aminoethyl)-6-(3-chloro-thiophen-2-yl)-7-iodo-3-hydropyrrolo[3,2-d]pyrimidin-4-one hydrochloride (173 mg) was added t-butylacetyl chloride (95 mg) and the mixture was stirred at room temperature for a short time, followed by adding triethylamine (1.0 mL) and stirring at room temperature for 2 hours. To the reaction solution was added water (1.0 mL) and further the solution was stirred at room temperature overnight. The obtained solution was extracted with ethyl acetate (10 mL×2). The organic layer was washed with saturated brine, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by column chromatography on silica gel (using ethyl acetate only) to obtain the title compound (160 mg, yield: 88%). The NMR data and ESI/MS data of the compound are given below.

¹H-NMR(400 MHz, DMSO-d₆) δ(ppm): 0.84(s,9H), 1.81(d,J=3.67, 2H), 3.25-3.34(m,2H), 4.05-4.12(m,1H), 4.44-4.50(m,1H), 7.28(d,J=5.36, 1H), 7.69(t,J=5.86, 1H), 7.92(d,J=3.67, 1H), 8.00(d,J=5.36, 1H), 12.25(brs,1H).

ESI/MS m/e: 519.1(M⁺+H, C₁₈H₂₀ClIN₄O₂S)

Example 30

Synthesis of N-{2-[7-(1H-pyrazol-4-yl)-6-(3-chloro-thiophen-2-yl)-4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-t-butylacetylamide (Compound No. 629)

To a screw-cap vial were transferred N-{2-[6-(3-chloro-thiophen-2-yl)-4-oxo-7-iodo-3-hydropyrrolo[3,2-d]pyrimidin-5-yl]ethyl]-t-butylacetylamide (26 mg), palladium acetate (2.2 mg), triphenylphosphine (5.2 mg), sodium carbonate (26 mg) and 4-(4,4,5,5,-tetramethyl-[1,3,2]-dioxaborolan-2-yl)-1H-pyrazole (19.4 mg), and flushed with nitrogen. A 2:1 dimethylformamide:water solution (1 mL) was added to the reaction mixture and the mixture was stirred at 80° C. for 12 hours. Saturated brine was added to the obtained solution and extracted with ethyl acetate. The organic layer was concentrated and purified by fraction HPLC to obtain the title compound (5.2 mg, yield 23%). The HPLC retention time, NMR data and ESI/MS data of the compound are given below.

HPLC retention time=10.9 (min)

¹H-NMR(400 MHz, DMSO-d₆) δ(ppm): 0.85(s,9H) 1.84(d,J=1.68, 2H), 3.30-3.38(m,2H), 4.04-4.11(m,1H), 4.35-4.40(m,1H), 7.34(d,J=5.38,1H), 7.44(brs,2H), 7.76(t,J=5.60,1H), 7.93(s,1H), 8.05(d,J=5.38, 1H), 12.17(brs,1H).

EMS/MS m/e 459.3 (M+H⁺, C₂₁H₂₃ClN₆O₂S

Example 31

Synthesis of 5-(2-aminoethyl)-6-(3-chloro-thiophen-2-yl)-7-pyridin-3-yl-3-hydropyrrolo[3,2-d]pyrimidin-4-one (Compound No. 209) dihydrochloride

(t-butoxy)-N-{2-[6-(3-chloro-thiophen-2-yl)-7-pyridin-3-yl-4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-5-yl]-ethyl}carboxyamide (1.68 g) was dissolved in methanol (10.0 mL), followed by adding 4 mol/L hydrochloric acid/1,4-dioxane solution (2.0 mL) thereto and stirring at 60° C. for 12 hours. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. The residue was dried under reduced pressure to obtain the title compound (1.64 g, a quantitative yield). The ESI/MS data of the compound are given below.

ESI/MS m/e: 371.9(M⁺+H, C₁₇H₁₄ClN₅OS 2HCl)

Example 32

Synthesis of 1-{2-[6-(3-chloro-thiophen-2-yl)-4-oxo-7-pyridin-3-yl-3-hydropyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-3-phenylurea (Compound No. 793)

To an N,N-dimethylformamide (1.0 mL) solution of 5-(2-aminoethyl)-6-(3-chloro-thiophen-2-yl)-7-pyridin-3-yl-3-hydropyrrolo[3,2-d]pyrimidin-4-one dihydrochloride (25 mg) was added phenylisocyanate (20 mg) and the mixture was stirred at room temperature for a short time, followed by adding triethylamine (0.2 mL) and stirring at room temperature for 2 hours. Saturated brine was added to the obtained solution and extracted with ethyl acetate. The reaction solution was distilled off under reduced pressure, and the residue was purified by fraction HPLC to obtain the title compound (8 mg, yield 29%). The HPLC retention time and ESI/MS data of the compound are given below.

HPLC retention time=6.6 (min)

ESI/MS m/e: 491.04(M⁺+H, C₂₄H₁₉ClN₆O₂S

Example 33

Synthesis of 4-fluoropiperidine-1-[2-[6-(3-chloro-thiophen-2-yl)-4-oxo-7-pyridin-3-yl-3-hydropyrrolo [3,2-d]pyrimidin-5-yl]-ethyl}-carboxyamide (Compound No. 550)

To a chloroform (1.0 mL) solution of 5-(2-aminoethyl)-6-(3-chloro-thiophen-2-yl)-7-pyridin-3-yl-3-hydropyrrolo [3,2-d]pyrimidin-4-one dihydrochloride (25 mg) were added triethylamine (0.078 mL) and triphosgene (17 mg) and the mixture was stirred at room temperature for a short time, and 4-fluoropiperidine (12 mg) was added thereto followed by stirring at room temperature for 3 hours. Saturated brine was added to the obtained solution and extracted with ethyl acetate. The reaction solution was distilled off under reduced pressure, and the residue was purified by fraction HPLC to obtain the title compound (1.2 mg, yield 5%). The HPLC retention time and ESI/MS data of the compound are given below.

HPLC retention time=6.9 (min)

ESI/MS m/e: 501.41(M⁺+H, C₂₃H₂₂ClFN₆O₂S)

Example 34

Synthesis of 5-[2-(bis(cyclopropylmethyl)amino) ethyl]-6-(3-chloro-thiophen-2-yl)-7-pyridin-3-yl-3-hydropyrrolo[3,2-d]pyrimidin-4-one (Compound No. 1057)

To an N,N-dimethylformamide (1.0 mL) solution of 5-(2-aminoethyl)-6-(3-chloro-thiophen-2-yl)-7-pyridin-3-yl-3-hydropyrrolo[3,2-d]pyrimidin-4-one dihydrochloride (25 mg) were added cyclopropyl aldehyde (5 mg), sodium triacetoxy borohydride (24 mg) and acetic acid (0.1 mL) and the mixture was stirred at room temperature for 10 hours. Saturated brine was added to the obtained solution and extracted with ethyl acetate. The reaction solution was distilled off under reduced pressure, and the residue was purified by fraction HPLC to obtain the title compound (10 mg, yield 36%). The HPLC retention time and ESI/MS data of the compound are given below.

HPLC retention time=5.4 (min)

ESI/MS m/e: 482.0(M⁺+H, C₂₅H₂₆ClFN₅OS)

Example 35

Synthesis of N-{2-[6-(3-chloro-thiophen-2-yl)-4-oxo-7-pyridin-3-yl-3-hydropyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-t-butylacetylamide (Compound No. 626)

To an N,N-dimethylacetamide (1.0 mL) solution of 5-(2-aminoethyl)-6-(3-chloro-thiophen-2-yl)-7-pyridin-3-yl-3-hydropyrrolo[3,2-d]pyrimidin-4-one dihydrochloride (25 mg) was added t-butylacetyl chloride (23 mg) and the mixture was stirred at room temperature for a short time, followed by adding triethylamine (0.2 mL) and stirring at room temperature for 2 hours. Water (0.2 mL) was added to the reaction solution and the solution was stirred again at room temperature overnight. Saturated brine was added to the obtained solution and extracted with ethyl acetate. The reaction solution was distilled off under reduced pressure, and the residue was purified by fraction HPLC to obtain the title compound (19 mg, yield 72%). The HPLC retention time and ESI/MS data of the compound are given below.

HPLC retention time=7.6 (min)

ESI/MS m/e: 470.1(M⁺+H, C₂₃H₂₄ClN₅O₂S)

Example 36

Synthesis of 1-methyl-cyclohexane-{2-[6-(3-chloro-thiophen-2-yl)-4-oxo-7-pyridin-3-yl-3-hydropyrrolo [3,2-d]pyrimidin-5-yl]-ethyl}-carboxyamide (Compound No. 684)

To an N,N-dimethylformamide (1.0 mL) solution of 5-(2-aminoethyl)-6-(3-chlorothiophen-2-yl)-7-pyridin-3-yl-3-hydropyrrolo[3,2-d]pyrimidin-4-one dihydrochloride (25 mg) were added 1-methyl-cyclohexanecarboxylic acid (24 mg), 1-ethyl-3-(3′-dimethylaminopropyl)carboxyamide hydrochloride (43 mg), N-hydroxybenzotriazole (8 mg) and triethylamine (0.2 mL) and the mixture was stirred at room temperature for 10 hours. Saturated brine was added to the obtained solution and extracted with ethyl acetate. The reaction solution was distilled off under reduced pressure, and the residue was purified by fraction HPLC to obtain the title compound (11 mg, yield 41%). The HPLC retention time and ESI/MS data of the compound are given below.

HPLC retention time=8.2 (min)

ESI/MS m/e: 496.0(M⁺+H, C₂₅H₂₆ClN₅O₂S)

Example 37

Synthesis of N-{2-[6-(3-chloro(2-thienyl))-4-oxo-7-(3-pyridyl)-3-hydropyrrolo[3,2-d]pyrimidin-5-yl]ethyl}acetamide (Compound No. 217)

To a 1,4-dioxane (6.0 mL) and methanol (1.0 mL) solution of (t-butoxy)-N-{2-[6-(3-chloro(2-thienyl))-4-oxo-7-(3-pyridyl)(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide (356 mg) was added 4 mol/L hydrochloric acid/dioxane solution (0.75 mL) and the mixture was stirred 60° C. for 1 hour. The reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure. The residue was dried under reduced pressure to obtain crude product (370 mg). To a dimethylacetamide solution (2.0 mL) of the reaction product (26 mg) were added chloroacetyl (10 mg) and triethylamine (0.2 mL) and the mixture was stirred at room temperature for 1 hour, followed by adding water (0.2 mL) and further stirring at room temperature for 1 hour. Purification by fraction HPLC was performed to obtain the title compound (15 mg, yield 57%). The HPLC retention time, NMR data and ESI/MS data of the compound are given below.

HPLC retention time=5.7 (min)

¹H-NMR(400 MHz, DMSO-d₆) δ(ppm): 1.65(s,3H), 3.31-3.41(m,2H), 4.16(m,1H), 4.50(m,1H), 7.29(m,1H), 7.61(dd,J=5.12,J=8.08, 1H), 7.86(m,1H), 7.92(m,1H), 8.01(m,2H), 8.54(d,J=5.12,1H), 8.64(s,1H), 12.38(brs,1H).

ESI/MS m/e: 414.4(M⁺+H, C₁₉H¹⁶ClN₅O₂S)

Example 38

Synthesis of 6-(3-chloro(2-thienyl))-7-(3-pyridyl)-5-[2-quinazolin-4-ylamino]ethyl]-3-hydropyrrolo [3,2-d]pyrimidin-4-one (Compound No. 84)

A 4 mol/L hydrochloric acid/dioxane solution (0.75 mL) was added to a 1,4-dioxane (6.0 mL) and methanol (1.0 mL) solution of (t-butoxy)-N-{2-[6-(3-chloro(2-thienyl))-4-oxo-7-(3-pyridyl)(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide (356 mg) and the mixture was stirred at 60° C. for 1 hour. The reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure. The residue was dried under reduced pressure to obtain a crude product (370 mg). To a dimethylacetamide (2.0 mL) solution of the reaction product (32 mg) were added 4-chloroquinazoline (13 mg) and triethylamine (16 mg) and the solution was stirred at 70° C. for 2 hours. The reaction solution was cooled to room temperature, and purification by fraction HPLC was performed to obtain the title compound (21 mg, yield 54%). The HPLC retention time, NMR data and ESI/MS data of the compound are given below.

HPLC retention time=5.6 (min)

¹H-NMR(400 MHz, DMSO-d₆) δ(ppm): 4.01-4.06(m,2H), 4.55(m,1H), 4.96(m,1H), 7.08(m,1H), 7.47(dd,J=4.88,J=8.04,1H), 7.72-7.78(m,3H), 7.83(m,1H), 7.90(s,1H), 8.02(t,J=7.68,1H), 8.23(d,J=8.52,1H), 8.46(d,J=5.12,1H), 8.52(s,1H), 8.67(s,1H), 10.18(m,1H), 12.30(brs,1H).

ESI/MS m/e: 500.4(M⁺+H, C₂₅H₁₈ClN₇OS)

Example 39

Synthesis of ethyl 3-(4-oxo-7-(3-pyridyl)-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)propanate (Compound No. 35)

To an isopropyl alcohol (80 mL) solution of ethyl 3-β-amino-2-(methoxycarbonyl)-4-(3-pyridyl)pyrrolyl] propanate (4.380 g) was added formamidine acetate (7.184 g) and the mixture was stirred at 90° C. for 10 hours. The reaction solution was cooled to room temperature, and the solid was subjected to fractional filtration. The extractant was distilled off under reduced pressure. To the residue was added water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with sodium sulfate, which was then subjected to fractional filtration. Then, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:ethanol=7:1), to obtain the title compound (0.747 g, yield 17%). The HPLC retention time, NMR data and ESI/MS data of the compound are given below.

HPLC retention time=5.6 (min)

¹H-NMR(400 MHz, DMSO-d₆) δ(ppm): 1.11(t,J=7.08,3H), 2.95(t,J=6.96,2H), 4.03(dd,J=6.96,J=14.28,2H), 4.63(t,J=6.84,2H), 7.81(dd,J=5.12,J=8.04,1H), 7.99(s,1H), 8.22(s,1H), 8.60(d,J=5.12,1H), 8.81(d,J=8.04,1H),9.38(s,1H), 12.29(s,1H).

ESI/MS m/e: 313.2(M⁺+H, C₁₆H₁₆N₄O₃)

Example 40

Synthesis of 3-(4-oxo-7-(3-pyridyl)(3-hydropyrrolo[3,2-d]pyrimidin-5-yl))-N-phenylpropaneamide (Compound No. 30)

Water (0.40 mL) and a 5 M aqueous sodium hydroxide solution (0.18 mL) were added to a 1,4-dioxane (3.0 mL) solution of ethyl 3-(4-oxo-7-(3-pyridyl)-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)propanate (91 mg) and the mixture was stirred at room temperature for 2 hours. The reaction solution was neutralized with acetic acid, and the resulting solid was filtered and washed with water and ethyl acetate to obtain a crude product (78 mg). 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (41 mg) and pyridine (0.2 mL) were added to a mixed solution of dichloromethane (1.0 mL) and dimethylacetamide (1.0 mL) of the reaction product (20 mg) and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added aniline (20 mg) and the solution was stirred at 40° C. overnight. Methanol was added to stop the reaction, and the solvent was distilled off under reduced pressure. The residue was purified by fraction HPLC to obtain the title compound (19 mg, yield 76%). The HPLC retention time, NMR data and ESI/MS data of the compound are given below.

HPLC retention time=6.1 (min)

¹H-NMR(400 MHz, DMSO-d₆) δ(ppm): 2.97(t,J=6.58,2H) 4.69(t,J=6.48,2H),6.99(t,J=7.46,1H), 7.24(t,J=7.92,2H), 7.51(d,J=8.56,2H), 7.78(dd,J=5.50,J=7.94,1H), 7.99(s,1H), 8.18(s,1H), 8.57(d,J=5.40,1H), 8.78(d,J=8.04,1H), 9.36(s,1H), 9.96(s,1H), 12.30(brs,1H).

ESI/MS m/e: 360.2(M⁺+H, C₂₀H₁₇N₅O₂)

Example 41

Synthesis of 6-chloro-5-benzyl-7-(3-pyridyl)-3-hydropyrrolo[3,2-d]pyrimidin-4-one (Compound No. 1180)

N-chlorosuccinimide (57 mg) was added to a dimethylformamide (2.0 mL) solution of 5-benzyl-7-(3-pyridyl)-3-hydropyrrolo[3,2-d]pyrimidin-4-one (65 mg) and the mixture was stirred at room temperature for 2 hours. N-chlorosuccinimide (57 mg) was added to the reaction mixture and further the mixture was stirred at room temperature for 2 hours. Water (0.2 mL) was added to stop the reaction, and purification by fraction HPLC gave the title compound (33 mg, yield 46%). The HPLC retention time, NMR data and ESI/MS data of the compound are given below.

HPLC retention time=8.0 (min)

¹H-NMR(400 MHz, DMSO-d₆) δ(ppm): 5.82(s,2H), 7.22-7.36(m,5H), 7.72(dd,J=5.12,J=8.04,1H), 8.00(s,1H), 8.42(m,1H), 8.64(d,J=5.12,1H),9.07(s,1H), 12.41(brs,1H).

ESI/MS m/e: 337.3(M⁺+H, C₁₈H₁₃ClN₄O

Example 42

Synthesis of 7-(3-pyridyl)-4-oxo-6-cyclopropyl-3-hydropyrrolo[3,2-d]pyrimidine (Compound No. 1178)

To a 100 mL branched flask was transferred ethyl 3-amino-4-(3-pyridyl)-5-cyclopropyl pyrrole-2-carboxylate (118 mg), and isopropylalcohol (40 mL) and formamidine acetate (1.35 g) were added thereto and heated at 95° C. for 13 hours with stirring. After the completion of the reaction, the solvent was concentrated under reduced pressure. To the concentrated residue were added water (20 mL) and ethyl acetate (20 mL) for separation. The aqueous layer was extracted again with 20 mL ethyl acetate. The organic layer was washed twice with 20 mL water, dehydrated and dried with magnesium sulfate, filtered and concentrated to obtain a crude product (91 g). The crude product was washed 3 times with 1 mL methanol to yield the title compound (49 mg, yield 45%). The ESI/MS data of the compound are given below.

HPLC retention time=4.2 (min)

ESI/MS m/e: 253.1(M⁺+H, C₁₄H₁₂N₄O)

Example 43

Synthesis of (t-butoxy)-N-{2-[6-(3-chloro(2-thienyl))-4-oxo-7-(trifluoromethyl)(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide (Compound No. 947)

Under nitrogen atmosphere, a dry dimethylformamide suspension (10 mL) of cadmium (2.24 g) was cooled on ice with stirring, and dibromodifluoromethane (1.5 mL) was added thereto, followed by stirring at room temperature for 3 hours. Dry hexamethylphosphoramide (10 mL) was added to the reaction solution and cooled on ice, and copper (I) bromide (1.16 g) was added to the reaction mixture and the mixture was stirred at room temperature for 1 hour to obtain a copper trifluoromethyl compound suspension.

The copper trifluoromethyl compound suspension (10 mL) was added to a dry dimethylformamide solution (3 mL) of (t-butoxy)-N-{2-[6-(3-chloro(2-thienyl))-7-iodo-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide (115 mg) and the solution was stirred at 65° C. for 6 hours. An aqueous ammonium chloride solution was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, concentrated, and purified by chromatography on silica gel, to obtain the title compound (35 mg, 34%). The HPLC retention time, NMR data and ESI/MS data of the compound are given below.

HPLC retention time=12.1 (min)

¹H-NMR(270 MHz,CDCl₃)δ(ppm): 1.32(s,9H), 3.35-3.60(m,2H), 4.00-4.30(m,1H), 4.40-4.70(m,1H), 7.11(d,J=5.1 Hz,1H), 7.61(d,J=5.4 Hz,1H), 7.95-8.10(m,₁H).

ESI/MS m/e: 463.2 (M⁺+H, C₁₈H₁₈ClF₃N₄O₃S)

Example 44

Synthesis of 6-phenyl-7-(3-pyridyl)-3-hydropyrrolo[3,2-d]pyrimidin-4-one (Compound No. 2445)

An N,N-dimethylformamide/water (2:1) solution (1.0 mL) of 6-chloro-7-(3-pyridyl)-3-hydropyrrolo[3,2-d]pyrimidin-4-one (40 mg), phenyl boric acid (59 mg), and potassium acetate (78 mg) was subjected to deaeration, and a small amount of [1,1′-bis(diphenylphosphino)ferrocene] palladium (II) chloride dichloro-methane (1:1) complex was added thereto. The reaction mixture was heated at 140° C. for 5 minutes by using microwaves. The solvent was distilled off under reduced pressure and the residue was separated to ethyl acetate and aqueous layers. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and brine and dried over sodium sulfate. The sodium sulfate was filtered, and solvent was distilled off under reduced pressure. The residue was purified by chromatography on silica gel (0-5% methanol/ethyl acetate), and further purified by fraction HPLC to obtain the title compound (6.3 mg, yield 10%). The HPLC retention time, NMR data and ESI/MS data of the compound are given below.

HPLC retention time: 4.0 (min)

¹H-NMR(400 MHz,CD₃OD)δ(ppm): 7.50(m,5H), 7.86(dd,J=5.7, J=8.2, 1H), 7.98(s,1H), 8.44(dt,J=1.6, J=8.2, 1H), 8.62(d,J=5.7, 1H), 8.94(s,1H).

ESI/MS m/e: 289.1(M⁺+H, C₁₇H₁₂N₄O)

Example 45

Synthesis of ethyl 4-(4-oxo-3-hydropyrrolo [3,2-d]pyrimidin-5-yl)butanoate (Compound No. 2501)

An ethyl 4-[3-amino-2-(ethoxycarbonyl)pyrolyl] butanoate hydrochloride (20.1 g) was dissolved in dichloromethane (400 mL), and saturated aqueous sodium hydrogen carbonate (400 mL) was added thereto. The reaction mixture was vigorously stirred for 30 minutes, and two layers were separated. The aqueous layer was extracted with dichloromethane, and combined organic layer was washed with saturated brine, and dried over magnesium sulfate. The magnesium sulfate was filtered, and the solvent was distilled off under reduced pressure to obtain ethyl 4-[3-amino-2-(ethoxycarbonyl) pyrolyl]butanoate (18.0 g). This compound was dissolved in isopropylalcohol (400 mL), and formamidine acetate (9.78 g) was added thereto. This mixture was heated for 150 minutes to reflux. The solvent was distilled off under reduced pressure and the residue was separated to dichloromethane and aqueous layers. The aqueous layer was extracted with dichloromethane, and the combined organic layer was washed with 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate, and saturated brine, which was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (13.0 mg, yield 78%). The NMR data and ESI/MS data of the compound are given below.

¹H-NMR(400 MHz,DMSO-d₆)δ(ppm): 1.14(t,J=7.1, 3H), 2.01 (pent,J=7.0, 2H), 2.21(t,J=7.5, 2H), 3.99(q,J=7.1, 2H), 4.38(t,J=6.7, 2H), 6.33(d,J=2.9, 1H), 7.41(d,J=2.9, 1H), 7.76(s, 1H), 11.86(brs,1H).

ESI/MS m/e: 250.1(M⁺+H, C₁₂H₁₅N₃O₃)

Example 46

Synthesis of ethyl 4-(7-iodo-4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoate (Compound No. 2502)

An N-iodosuccinimide (12.8 g) was added to a dichloromethane (350 mL) solution of ethyl 4-(4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoate (12.9 g), and stirred at room temperature overnight. A solid was extracted by filtration, washed with diethylether, and then dried under reduced pressure, to obtain the title compound (11.8 g, yield 61%). The filtration solution was concentrated under reduced pressure, ethyl acetate was added to the residue and vigorously stirred. The produced solid was extracted by filtration, washed with ethyl acetate and diethylether, and then dried under reduced pressure, to obtain the title compound (6.63 g, yield 34%). The NMR data and ESI/MS data of the compound are given below.

¹H-NMR(400 MHz,DMSO-d₆)δ(ppm): 1.13(t,J=7.1, 3H), 2.02 (pent,J=7.0, 2H), 2.22(t,J=7.4, 2H), 3.96(q,j=7.1, 2H), 4.39(t,J=6.7, 2H), 7.63(s, 1H), 7.85(s, 1H), 12.06(brs, 1H).

ESI/MS m/e: 376.0(M⁺+H, C₁₇H₁₈IN₃O₃)

Example 47

Synthesis of ethyl 4-(4-oxo-7-(3-pyridyl)₃-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoate (Compound No. 2512)

The title compound was obtained by using an ethyl 4-(7-iodo-4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoate and 3-pyridyl boric acid in a similar manner to that described in Example 28. The NMR data and ESI/MS data of the compound are given below.

¹H-NMR(400 MHz,DMSO-d₆)δ(ppm): 1.11(t,J=7.1, 3H), 2.09 (pent,J=7.0, 2H), 2.29(t,J=7.4, 2H), 3.96(q,j=7.1, 2H), 4.45(t,J=6.7, 2H), 7.41(m, 1H), 7.93(s, 1H), 8.06(s, 1H), 8.40(m, 2H), 9.21(m, 1H), 12.10(s, br, 1H).

ESI/MS m/e: 327.0(M⁺+H, C₁₇H₁₈N₄O₃)

Example 48

Synthesis of 4-(4-oxo-7-(3-pyridyl)₃-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoic acid (Compound No. 2503)

1M of aqueous lithium hydroxide solution (6.3 mL) was added to ethanol (24 mL) and water (3 mL) solution of ethyl-4-(4-oxo-7-(3-pyridyl)₃-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoate (0.78 g), and stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and water (5 mL) was added to the residue. 1M hydrochloric acid was added thereto to adjust pH to 4, and a produced solid was extracted by filtration, which was dried under reduced pressure, to obtain the title compound (0.75 g, quantitative yield). The NMR data and ESI/MS data of the compound are given below.

¹H-NMR(400 MHz,DMSO-d₆)δ(ppm): 2.07 (pent,J=7.0, 2H) 2.23(t,J=7.3, 2H), 4.46(t,J=6.7, 2H), 7.77(dd, J=4.3, J=8.2, 1H), 7.98(s, 1H), 8.24(s, 1H), 8.58(d, J=4.3, 1H), 8.79(d, J=8.2, 1H), 9.39(s, 1H), 12.12(brs, 1H), 12.24(brs, 1H)

ESI/MS m/e: 299.1(M⁺+H, C₁₅H₁₄N₄O₃)

Example 49

Synthesis of 4-(4-oxo-7-(3-pyridyl)₃-hydropyrrolo[3,2-d]pyrimidin-5-yl)-N-benzylbutanamide (Compound No. 2292)

A diisopropylethylamine (91 μL) and benzyl amine (29 μL) were added to solution of N,N-dimethylformamide (4 mL) of 4-(4-oxo-7-(3-pyridyl)₃-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoate (40 mg). Further, O-(7-azabenzotriazol-1-yl) N,N,N′,N′-tetramethyluronium hexafluorophosphate (74 mg) was added thereto, and the mixture solution was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and hot water was added to the residue. An insoluble portion was filtered off, the filtration solution was concentrated under reduced pressure, purified, to obtain the title compound (11. 6 mg, yield 22%). The HPLC retention time, NMR data and ESI/MS data of the compound are given below. The HPLC retention time: 5.1 (min)

¹H-NMR(400 MHz,DMSO-d₆)δ(ppm): 2.12(m, 4H), 4.23(d, J=6.0, 2H), 4.46(t,J=6.3, 2H), 7.22(m, 3H), 7.30(m, 2H), 7.73(dd, J=5.0, J=8.2, 1H), 7.98(s, 1H), 8.19(s, 1H), 8.33(t,J=6.0, 1H), 8.56(d, J=5.0, 1H), 8.74(d, J=8.2, 1H), 9.37(brs, 1H), 12.22(brs, 1H).

ESI/MS m/e: 388.1(M⁺+H, C₂₂H₂₁N₅O₂)

Example 50

Synthesis of ethyl 4-(6-chloro-4-oxo-7-(3-pyridyl)-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoate (Compound No. 2504)

An ethyl 4-(4-oxo-7-(3-pyridyl)-3-hydropyrrolo [3,2-d]pyrimidin-5-yl)butanoate (1.72 g) was dissolved in dichloromethane (63 mL) by heating, and cooled to 0° C. 2 mol/L of surfuryl chloride/dichloromethane solution (7.9 mL) was added dropwise, and stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and dichloromethane and saturated aqueous sodium hydrogen carbonate solution were added, and vigorously stirred. Two layers were separated, and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with saturated brine, and dried over sodium sulfate. The sodium sulfate was filtered, and the solvent was distilled off under reduced pressure to obtain the title compound (1.89 g, quantitative yield). The NMR data and ESI/MS data of the compound are given below.

¹H-NMR(400 MHz,DMSO-d₆)δ(ppm) 1.11(t,J=7.1, 3H), 2.06 (pent,J=7.0, 2H), 2.37(t,J=7.2, 2H), 3.94(q,J=7.1, 2H), 4.58(t,J=6.7, 2H), 7.51(dd, J=4.7, J=7.9, 1H), 7.93(d,J=3.0, 1H), 8.13(dt, J=1.9, J=7.9, 1H), 8.54(d,J=7, 1H), 8.94(s, 1H), 12.28(brs, 1H).

ESI/MS m/e: 361.1(M⁺+H, C₁₇H₁₇N₄O₃)

Example 51

Synthesis of 4-(6-chloro-4-oxo-7-(3-pyridyl)-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoic acid (Compound No. 2505)

1M of aqueous lithium hydroxide solution (8.6 mL) was added to ethanol (25 mL) solution of ethyl-4-(6-chloro-4-oxo-7-(3-pyridyl)₃-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoate (1.24 g), and stirred at room temperature overnight. 1M of hydrochloric acid (8.6 mL) was added thereto, the solvent was distilled off under reduced pressure, to obtain the title compound as a mixture (1.73 g) with lithium chloride. The NMR data and ESI/MS data of the compound are given below.

¹H-NMR(400 MHz,DMSO-d₆)δ(ppm): 2.02(m, 2H), 2.29(t,J=7.4, 2H), 4.57(t,J=6.9, 2H), 7.58(ddd,J=0.8, J=4.9, J=8.0, 1H), 7.94(s, 1H), 8.23(ddd,J=1.5, J=2.3, J=8.0, 1H), 8.57(dd,J=1.5, J=4.9, 1H), 8.98(dd,J=0.8, J=2.3, 1H), 12.16(brs, 1H), 12.39(brs, 1H).

ESI/MS m/e: 333.1(M⁺+H, C₁₅H₁₃ClN₄O₃ LiCl)

Example 52

Synthesis of 4-(6-chloro-4-oxo-7-(3-pyridyl)-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)-N-(cyclohexylmethyl)butanamide (Compound No. 2264)

A cyclohexanemethylamine (27 mg) and diisopropyl-ethylamine (84 μL) were added to a solution of N,N-dimethylformamide (1 mL) of 4-(6-chloro-4-oxo-7-(3-pyridyl)₃-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoate (40 mg). Further, O-(7-azabenzotriazol-1-yl)N,N,N′,N′-tetramethyluronium hexafluorophosphate (55 mg) was added thereto, and the mixture solution was stirred at room temperature for 2 hours. The reaction mixture was separated to ethyl acetate and aqueous layers. The organic layer was washed with 1 mol/L of aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate, and saturated brine, which was dried over sodium sulfate. The sodium sulfate was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (5% methanol/ethyl acetate) to obtain the title compound (35 mg, yield 68%). The HPLC retention time, NMR data and ESI/MS data of the compound are given below.

The HPLC retention time: 7.2 (min)

¹H-NMR(400 MHz,CD₃OD)δ(ppm): 0.09(m, 2H), 1.21(m, 3H), 1.42(m, 1H), 1.69(m, 5H), 2.16(m, 2H), 2.29(t,H=7.4, 2H), 2.95(d,J=7.0, 2H), 4.66(t,J=6.9, 2H), 7.53(ddd,J=0.9, J=5.0, J=8.0, 1H), 7.89(s, 1H), 8.22(ddd,J=1.6, J=2.2, J=8.0, 1H), 8.49(dd,J=1.6, J=5.0, 1H), 8.93(dd,J=0.9, J=2.2, 1H).

ESI/MS m/e: 428.2 (M⁺+H, C₂₂H₂₆ClN₅O₂)

Example 53

Synthesis of 4-[6-(3,4-dimethoxyphenyl)-4-oxo-7-(3-pyridyl) (3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]-N-(cyclohexylmethyl)butanamide (Compound No. 2269)

An N,N-dimethylformamide/water (2:1) solution (2 mL) of 4-(6-chloro-4-oxo-7-(3-pyridyl)(3-hydropyrrolo[3,2-d] pyrimidin-5-yl))-N-(cyclohexylmethyl)butanamide (50 mg), 3,4-dimethoxyphenyl boric acid (64 mg), and potassium acetate (57 mg) was subjected to deaeration, followed by flushing with nitrogen gas. A small amount of [1,1′-bis(diphenylphosphino) ferrocene]palladium (II) chloride dichloro-methane (1:1) complex body was added thereto. The reaction mixture was heated at 140° C. for 30 minutes by using microwave. The solvent was distilled off under reduced pressure and the residue was purified by column chromatography on silica gel (5-8% methanol/ethyl acetate), and further purified by fraction HPLC to obtain the title compound (12 mg, yield 16%). The HPLC retention time, NMR data and ESI/MS data of the compound are given below.

HPLC retention time: 8.0 (min)

¹H-NMR(400 MHz,CD₃OD)δ(ppm): 0.85(m,2H), 1.19(m, 3H) 1.35(m, 1H), 1.66(m, 5H), 2.01(m, 2H), 2.13(t, J=7.4, 2H), 2.88(d, J=6.8, 2H), 3.80(s, 3H), 3.91(s, 3H), 4.42(t,J=7.5, 2H), 7.00(dd,J=2.0, J=8.1, 1H), 7.03(d,J=2.0, 1H), 7.13(d,J=8.1, 1H), 7.81(dd,J=5.6, J=8.2, 1H), 7.99(s, 1H), 8.39(ddd,J=1.4, J=2.1, J=8.2, 1H), 8.52(d,J=5.6, 1H), 8.90(d,J=2.1, 1H).

ESI/MS m/e: 530.3(M⁺+H, C₃₀H₃₅N₅O₄)

Example 54

Synthesis of ethyl 4-{7-iodo-4-oxo-3-[(phenylmethoxy)methyl]-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoate

A sodium hydride (521 mg) was added to solution of N,N-dimethylformamide (60 mL) of ethyl 4-(7-iodo-4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoate (4.07 g) in a small amount by each, and the mixture solution was stirred at room temperature for 30 minutes. A benzylchloromethylether (2.04 g) was added dropwise, and the mixture solution was further stirred for 2 hours. The solvent was distilled off under reduced pressure to separate the residue to ethyl acetate and aqueous layers. The organic layer was washed with water and saturated brine, and dried over sodium sulfate. The sodium sulfate was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (15-30% ethyl acetate/cyclohexane), to obtain the title compound (3.80 g, yield 71%). The NMR data and ESI/MS data of the compound are given below.

¹H-NMR(400 MHZ,CDCl₃)δ(ppm): 1.25(t,J=7.1, 3H), 2.18(pent,J=7.0, 2H), 2.32(t,J=7.2, 2H), 4.12(q,J=7.1, 2H), 4.51(t,J=6.9, 2H), 4.65(s, 2H), 5.50(s, 2H), 7.22(s, 1H), 7.29(m, 1H), 7.33(m, 4H), 8.03(s, 1H).

ESI/MS m/e: 496.1(M⁺+H, C₂₀H₂₂IN₃O₄)

Example 55

Synthesis of ethyl-4-{7-(1-methylpyrazol-4-yl)-4-oxo-3-[(phenylmethoxy)methyl]-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoate

The title compound was obtained by using ethyl 4-{7-iodo-4-oxo-3-[(phenylmethoxy)methyl]-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoate and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazol in a similar manner to that in Example 28. The NMR data and ESI/MS data of the compound are given below.

¹H-NMR(400 MHz,CD₃OD)δ(ppm): 1.16(t,J=7.1, 3H), 2.16(pent,J=7.0, 2H), 2.33(t,J=7.2, 2H), 3.92(s,3H), 3.02(q,J=7.1, 2H), 4.49(t,J=6.7, 2H), 4.68(s, 2H), 5.56(s, 2H), 7.22(m, 1H), 7.28(m, 2H), 7.33(m, 2H), 7.54(s, 1H), 7.86(d,J=0.6, 1H), 8.03(s, 1H), 8.10(s, 1H).

ESI/MS m/e: 450.3(M⁺+H, C₂₄H₂₇N₅O₄)

Example 56

Synthesis of 4-[6-chloro-7-(1-methylpyrazol-4-yl)-4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoic acid (Compound No. 2506)

Solution of concentrated hydrochloric acid (3 mL) of ethyl-4-{6-chloro-7-(1-methylpyrazol-4-yl)-4-oxo-3-[(phenylmethoxy)methyl]-3-hydropyrrolo[3,2-d]pyrimidin-5-yl) butanoate was heated for 1 hour to reflux. The solvent was distilled off under reduced pressure, and methanol solution (3 mL) of 2 mol/L ammonia was added to the residue. The solvent was distilled off under reduced pressure, and 1 mol/L of aqueous citric acid solution was added to the residue. A produced solid was extracted by filtration, washed with water and diethylether, and then dried under reduced pressure, to obtain the title compound (133 mg, yield 87%). The NMR data and ESI/MS data of the compound are given below.

¹H-NMR(400 MHz,DMSO-d₆)δ(ppm): 1.97(pent,J=7.0, 2H), 2.23(t,J=7.4, 2H), 3.91(s,3H), 4.50(t,J=6.8, 3H), 7.91(d,J=3.6, 1H), 8.04(s, 1H), 8.24(s, 1H), 12.11(s, 1H), 12.17(d,J=3.6, 1H).

ESI/MS m/e: 336.2 (M⁺+H, C₁₄H₁₄ClN₅O₃)

Example 57

Synthesis of 4-[6-chloro-7-(1-methylpyrazol-4-yl)-4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-5-yl]]-N-[(4-methylphenyl)methyl]butanamide (Compound No. 2507)

A 4-methylbenzyl amine (29 mg) and a diisopropylethylamine (84 μm) were added to a solution of an N,N-dimethylformamide (1 mL) of 4-[6-chloro-7-(1-methylpyrazol-4-yl)-4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)-butanoate (40 mg). An o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (55 mg) was further added, and the mixture solution was stirred at room temperature overnight. An ethyl acetate and 1 mol/L of an aqueous citric acid solution were added to the reaction mixture, and separated to two layers. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over sodium sulfate. The sodium sulfate was filtered off, and the solvent was distilled off under reduced pressure, to obtain the title compound (67 mg, quantitative yield). The compound was not further purified, but used for the following reaction. The ESI/MS data of the compound is given below.

ESI/MS m/e: 439.2 (M⁺+H, C₂₂H₂₃ClN₆O₂)

Example 58

Synthesis of 4-[6-(3,4-dimethoxyphenyl)-7-(1-methylpyrazol-4-yl)-4-oxo-7-(3-hydropyrrolo [3,2-d]pyrimidin-5-yl)]-N-[(4-methylphenyl)methyl] butanamide (Compound No. 2345)

An N,N-dimethylformamide/water (2:1) solution (2 mL) of 4-[6-chloro-7-(1-methylpyrazol-4-yl)-4-oxo (3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]-N-[(4-methylphenyl) methyl] butanamide (65 mg), 3,4-dimethoxyphenyl boric acid (81 mg), and potassium acetate (73 mg) was subjected to deaeration, followed by flushing with nitrogen gas. A small amount of [1,1′-bis(diphenylphosphino)ferrocene]palladium (II) chloride dichloro-methane (1:1) complex body was added thereto. The reaction mixture was heated at 160° C. for 45 minutes by using microwaves. The solvent was distilled off under reduced pressure and the residue was purified by column chromatography on silica gel (5-8% methanol/ethyl acetate), and further purified by fraction HPLC to obtain the title compound (4.4 mg, yield 7%). The HPLC retention time, NMR data and ESI/MS data of the compound are given below.

HPLC retention time: 8.2 (min)

¹H-NMR(400 MHz,CD₃OD)δ(ppm): 1.98(m,2H), 2.13(t,J=7.5, 2H), 2.29(2, 3H), 3.79(s, 3H), 3.82(s, 3H), 3.91(s, 3H), 4.18(s, 2H), 4.36(t,J=7.4, 2H), 6.98(m, 2H), 7.07(m, 4H), 7.12(d,J=7.9, 1H), 7.28(2, 1H), 7.66(s, 1H), 7.97(2, 1H).

ESI/MS m/e: 541.1(M⁺+H, C₃₀H₃₂N₆O₄)

Example 59

Synthesis of ethyl-4-(6-cyclopropyl-4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoate (Compound No. 2508)

The title compound was obtained by using ethyl-4-β-amino-5-cyclopropyl-2-(ethoxycarbonyl)pyrolyl] butanoate hydrochloride in a similar manner to that in Example 45. The NMR data and ESI/MS data of the compound are given below.

¹H-NMR(400 MHz,DMSO-d₆)δ(ppm): 0.74 (m, 2H), 1.00 (m, 2H) 1.13(t,J=7.2, 3H), 1.93-2.06(m, 3H), 2.31(t,J=7.4, 2H), 3.98(dd,J=7.2, J=14.2, 2H), 4.52(t,J=7.0, 2H), 6.00(s, 1H), 7.71(s, 1H), 11.76(brs, 1H).

ESI/MS m/e: 290.2(M⁺+H, C₁₅H₁₉N₃O₃)

Example 60

Synthesis of ethyl-4-(6-cyclopropyl-7-iodo-4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoate (Compound No. 2509)

A dichloromethane (40 mL) solution of an ethyl-4-(6-cyclopropyl-4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-5-yl) butanoate (1.58 g) and an N-iodosuccinimide (1.35 g) was stirred at room temperature for 2 hours. Water was added, and the mixture solution was further stirred for 30 minutes. A solid was extracted by filtration, washed by water and ethyl acetate, and dried under reduced pressure, to obtain the title compound (1.82 g, yield 80%). The filtration solution was separated to ethyl acetate and aqueous layers, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over a magnesium sulfate. The magnesium sulfate was filtered off, and the solvent was distilled off under reduced pressure. A produced solid was extracted by filtration, washed with ethyl acetate, and dried under reduced pressure, to obtain the title compound (0.35 mg, yield 15%). The NMR data and ESI/MS data of the compound are given below.

¹H-NMR(400 MHz,DMSO-d₆)δ(ppm): 0.89(m, 2H), 1.08-1.15(m, 5H), 1.80(m, 1H), 2.01(m, 2H), 2.31(t,J=7.3, 2H), 3.96(dd,J=7.0, J=14.3, 2H), 4.57(t,J=7.2, 2H), 7.82(s, 1H), 12.00(brs, H).

ESI/MS m/e: 416.1(M⁺+H, C₁₅H₁₈IN₃O₃)

Example 61

Synthesis of ethyl-4-(6-cyclopropyl-4-oxo-7-(3-pyridyl)-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoate (Compound No. 2510)

The title compound was obtained by using ethyl-4-(6-cyclopropyl-7-iodo-4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-5-yl) butanoate and 3-pyridyl boric acid in a similar manner to that in Example 28. The NMR data and ESI/MS data of the compound are given below.

¹H-NMR(400 MHz,DMSO-d₆)δ(ppm): 0.31(m, 2H), 1.01(m, 2H) 1.13(t,J=7.2, 3H), 2.06-2.13(m, 3H), 2.40(t,J=7.3, 2H), 3.98(dd,J=7.2, J=14.2, 2H), 4.61(t,J=7.2, 2H), 7.43(ddd,J=0.8, J=4.8, J=7.9, 1H), 7.82(s, 1H), 8.01(dt,J=2.0, J=8.1,1H), 8.46(dd,J=1.7, J=4.7, 1H), 8.83(dd,J=0.8, J=2.3, 1H), 11.99(brs, 1H).

ESI/MS m/e: 367.2(M⁺+H, C₂₀H₂₂N₄O₃)

Example 62

Synthesis of 4-(6-cyclopropyl-4-oxo-7-(3-pyridyl)-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoic acid (Compound No. 2363) hydrochloride

1M of aqueous lithium hydroxide solution (7.3 mL) was added to dioxane (25 mL) and water (10 mL) solution of ethyl-4-(6-cyclopropyl-4-oxo-7-(3-pyridyl)-3-hydropyrrolo [3,2-d]pyrimidin-5-yl) butanoate (1.06 g), and stirred at room temperature for 3 hours. 1M hydrochloric acid (10.2 mL) was added dropwise, and the solvent was distilled off under reduced pressure. An ethanol was added to a residue, a solid was extracted by filtration, washed with ethanol, and dried under reduced pressure, to obtain the title compound (1.10 g, quantitative yield). The NMR data and ESI/MS data of the compound are given below.

¹H-NMR(400 MHz,DMSO-d₆)δ(ppm): 0.39(m, 2H), 1.10(m, 2H) 2.07(m, 2H), 2.18(m, 1H), 2.33(t,J=7.4, 2H), 4.63(t,J=7.3, 2H), 7.95(s, 1H), 8.10(dd,J=5.7, J=8.1, 1H), 8.82(m, 2H), 9.16(d,J=1.8, 1H), 12.26(brs, 1H).

ESI/MS m/e: 339.0(M⁺+H, C₁₈H₁₈N₄O₃HCl)

Example 63

Synthesis of 4-(6-cyclopropyl-4-oxo-7-(3-pyridyl)(3-hydropyrrolo[3,2-d]pyrimidin-5-yl))-N-[(4-methylphenyl)methyl]butanamide (Compound No. 2331)

A diisopropylethylamine (70 μL) and a 4-methylbenzyl amine (15 mg) were added to solution of N,N-dimethylformamide (1.5 mL) of 4-(6-cyclopropyl-4-oxo-7-(3-pyridyl)-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoate (30 mg) and O-(7-azabenzotriazol-1-yl)N,N,N′,N′-tetramethyluronium hexafluorophosphate (46 mg). The reaction solution was stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure, and ethyl acetate and water were added to a residue, separated to two layers, and an aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over a sodium sulfate. The sodium sulfate was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by fraction HPLC, to obtain the title compound (3.1 mg, yield 9%). The HPLC retention time, NMR data and ESI/MS data of the compound are given below.

The HPLC retention time: 7.3 (min)

¹H-NMR(400 MHz,DMSO-d₆) δ(ppm): 0.27 (m, 2H), 0.93 (m, 2H), 2.01-2.11(m, 3H), 2.21-2.27(m, 5H), 4.21(d,J=5.9, 2H), 4.58(t,J=7.1, 2H), 7.10-7.15(m, 4H), 7.43(ddd,J=0.8, J=4.8, J=7.9, 1H), 7.82(s, 1H), 8.01(dt,J=2.0, J=8.1, 1H), 8.34(t,J=5.9, 1H), 8.46(dd,J=1.8, J=4.8, 1H), 8.84(dd,J=0.8, J=2.3, 1H).

ESI/MS m/e: 442.2(M⁺+H, C₂₆H₂₇NsO₂)

Example 64

Synthesis of ethyl-4-[6-cyclopropyl-7-(1-methylpyrazol-4-yl)-4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoate (Compound No. 2511)

The title compound was obtained by using ethyl-4-(6-cyclopropyl-7-iodo-4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoate and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazol in a similar manner to that in Example 28. The NMR data and ESI/MS data of the compound are given below.

¹H-NMR(400 MHz,DMSO-d₆)δ(ppm): 0.51(m, 2H), 1.13(m, 5H), 1.91(m, 1H), 2.03(m, 2H), 2.31(t,J=7.3, 2H), 3.89(s, 3H), 3.97(dd,J=7.2, J=14.2, 2H), 4.58(t,J=7.0, 2H), 7.80(d,J=3.3, 1H), 7.83(d,J=0.7, 1H), 8.03(s, 1H), 11.87(brs, 1H).

ESI/MS m/e: 370.2(M⁺+H, C₁₉H₂₃N₅O₃)]

Example 65

Synthesis of 4-[6-cyclopropyl-7-(1-methylpyrazol-4-yl)-4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-5-yl]butanoic acid (Compound No. 2364)

1M of aqueous lithium hydroxide solution (3.5 mL) was added to dioxane/water (4/1) solution (25 mL) of ethyl-4-[6-cyclopropyl-7-(1-methylpyrazol-4-yl)-4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-5-yl)butanoate (0.52 g) dropwise. The reaction solution was stirred at room temperature for 4 hours, and 1M hydrochloric acid (3.5 mL) was added thereto dropwise. The solvent was distilled off under reduced pressure, a residue was purified by column chromatography on silica gel (dichloromethane/methanol/acetate/water=240/30/3/2), a diethylether was added to the obtained solid, and finely pulverized. The solid was extracted by filtration, washed with diethylether, and dried under reduced pressure, to obtain the title compound (0.40 g, yield 84%). The NMR data and ESI/MS data of the compound are given below.

¹H-NMR(400 MHz,DMSO-d₆)δ(ppm): 0.51(m,2H), 1.12 (m,2H), 1.88-2.02(m,3H), 2.23(t,J=7.4,2H), 3.89(s,3H), 4.57(t,J=7.2,2H), 7.80(d,J=3.5,1H), 7.83(d,J=0.7,1H), 8.03(s,1H), 11.87(brs,1H).

ESI/MS m/e: 342.2 (M⁺+H, C₁₇H₁₉N₅O₃)

Example 66

Synthesis of 4-[6-cyclopropyl-7-(1-methylpyrazol-4-yl)-4-oxo-(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]-N-[(4-methylphenyl)methyl]butanamide (Compound No. 2332)

A diisopropylethylamine (78 μL) and a 4-methylbenzyl amine (13 mg) were added to a solution of N,N-dimethylformamide (1.0 mL) of 4-[6-cyclopropyl-7-(1-methylpyrazol-4-yl)-4-oxo-3-hydropyrrolo[3,2-d]pyrimidin-5-yl]butanoate (30 mg) and 0-(7-azabenzotriazol-1-yl)N,N,N′,N′-tetramethyluronium hexafluorophosphate (40 mg). The reaction solution was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, a residue was purified by fraction HPLC, to obtain the title compound (30 mg, yield 77%). The HPLC retention time and ESI/MS data of the compound are given below.

The HPLC retention time: 8.0 (min)

ESI/MS m/e: 445.3(M⁺+H, C₂₅H₂₈N₆O₂)

Example 67

Synthesis of 5-benzyl-7-(1-oxy(3-pyridyl))-3-hydropyrrolo[3,2-d]pyrimidin-4-one (Compound No. 2499)

30% aqueous hydrogen peroxide solution (92 mg).was added to an acetic acid (2 mL) solution of 5-benzyl-7-(3-pyridyl)-3-hydropyrrolo[3,2-d]pyrimidin-4-one (31 mg), and the solution mixture was stirred at room temperature overnight. The reaction mixture was cooled to room temperature, purified by fraction HPLC, to obtain the title compound (19 mg, yield 58%). The HPLC retention time, NMR data and ESI/MS data of the compound are given below.

The HPLC retention time: 5.8 (min)

¹H-NMR(400 MHz,DMSO-d₆)δ(ppm): 5.64(s,2H), 7.24-7.35(m,5H), 7.46(m,1H), 8.00(m,2H), 8.10(m,1H), 8.34(s,1H), 9.11(s,1H), 12.25(brs,1H).

ESI/MS m/e: 319.3(M⁺+H, C₁₈H₁₄N₄O₂)

Example 68

Synthesis of (t-butoxy)-N-{2-[6-(3-chloro(2-thienyl)-7-(5-methyl(1,2,4-oxadiazol-3-yl)-4-oxo-(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide (Compound No. 2126)

A (t-butoxy)-N-{2-[6-(3-chloro(2-thienyl))-7-cyano-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide (105 mg) was dissolved in ethanol (2.5 mL), 35 mg of a hydroxylamine hydrochloride and a diisopropylethylamine (100 mg) were added thereto, and the solution mixture was stirred overnight under overheat reflux. The solvent was distilled off under reduced pressure, a dichloromethane (2.5 mL) and water (2.5 mL) were added thereto, and an organic layer was fractionally extracted. An aqueous layer was further extracted with dichloromethane (2.5 mL), an organic layer was combined, dried over sodium sulfate, and the solvent was distilled off under reduced pressure, to obtain a residue (113 mg). This residue was dissolved in dichloromethane (2 mL), acetate (18 mg), 1-ethyl-3-(3′-dimethylaminopropyl) carbodiimide hydrochloride (57 mg), and triethylamine (41 μL) were added thereto, and the solution mixture was stirred at 40° C. for 1 hour. The reaction solution was concentrated, and purified by fraction HPLC, to obtain the title compound (7.2 mg, yield 6%). The HPLC retention time and ESI/MS data of the compound are given below.

The HPLC retention time: 9.5 (min)

ESI/MS m/e: 476.9(M⁺+H, C₂₀H₂₁ClN₆O₄S)

Example 69

Synthesis of (t-butoxy)-N-{2-[6-(3-chloro(2-thienyl)-7-(1,2,4-oxadiazol-3-yl)-4-oxo-(3-hydropyrrolo [3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide (Compound No. 2513)

A (t-butoxy)-N-{2-[6-(3-chloro(2-thienyl))-7-cyano-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide (105 mg) was dissolved in ethanol (2.5 mL), 35 mg of a hydroxylamine hydrochloride and a diisopropylethylamine (100 mg) were added thereto, and the solution mixture was stirred overnight under overheat reflux. The solvent was distilled off under reduced pressure, a dichloromethane (2.5 mL) and water (2.5 mL) were added thereto, and an organic layer was fractionally extracted. An aqueous layer was further extracted with dichloromethane (2.5 mL), an organic layer was combined, dried over sodium sulfate, and the solvent was distilled off under reduced pressure, to obtain a residue (113 mg). Meanwhile N,N-dimethylformamide (40 mg) was dissolved in diethylether (1 mL), phosphorus oxychloride (84 mg) was added thereto, and the solution mixture was stirred at room temperature for 1 hour, to obtain an oily compound. The produced oily compound was washed with diethylether (1 mL) twice, and suspended to a solvent mixture (3 mL) of 1,4-dioxane and diethylether. This suspension was added to the residue, and stirred at room temperature for 2 hours. The reaction solution was concentrated, water (5 mL) and ethyl acetate (5 mL) were added thereto, and an organic layer was separated. An aqueous layer was further extracted with ethyl acetate (5 mL), an organic layer was combined and concentrated, and then purified by fraction HPLC, to obtain the title compound (1.9 mg, yield 1.6%). The HPLC retention time and ESI/MS data of the compound are given below.

HPLC retention time: 9.1 (min).

ESI/MS m/e: 462.9(M⁺+H, C₁₉H₁₉ClN₆O₄S)

Example 70

Synthesis of (t-butoxy)-N-{2-[6-(3-hydroxyphenyl)-4-oxo-7-(3-pyridyl) (3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}carboxyamide (Compound No. 2121)

A t-butoxy)-N-(2-{4-oxo-6-[3-(phenylmethoxy)phenyl]-7-(3-pyridyl) (3-hydropyrrolo[3,2-d]pyrimidin-5-yl)}ethyl}carboxyamide (8.0 mg) was dissolved in ethanol, and palladium carbon (20 mg) was added thereto. The reaction system was substituted by hydrogen, and stirred at 60° C. overnight under atmospheric hydrogen pressure. The reaction solution was cooled to room temperature, and the palladium carbon was filtered off. The filtration solution was concentrated, purified by fraction HPLC, to obtain the title compound (4.0 mg, yield 60%). The HPLC retention time and ESI/MS data of the compound are given below.

HPLC retention time: 6.3 (min)

ESI/MS m/e: 448.0(M⁺+H, C₂₄H₂₅N₅O₄)

Examples 71 to 494

The following compounds of the present invention were synthesized according to any method of Example 1 to Example 70 by using corresponding starting materials and reaction agents. The ESI/MS data in the HPLC/mass spectrum analysis, the retention time of the compound in the HPLC analysis and purity under the following analysis conditions of each compound, and compound numbers corresponding to executed syntheses are summarized in Table 2. Compound numbers in the table represent compound numbers of Table 1 listed as the preferred specific examples.

TABLE 2
	Compound		ESI/MS	HPLC	Purity
Ex. no.	no.	Formula	m/e	min	(%)	Synthesis
71	19	C19H21N5O2	352.2	5.7	96	Ex. 40
72	27	C26H25N5O3	456.3	7.8	99	Ex. 40
73	29	C17H17N5O2	324.2	3.3	99	Ex. 40
74	40	C21H15Cl2N7OS	484.2	7.7	98	Ex. 38
75	80	C20H14BrClN6OS	503.2	6.8	100	Ex. 38
76	83	C26H19ClN6S2	515.4	10.4	96	Ex. 38
77	212	C19H14ClN5OS	395.4	11.7	86	Ex. 28
78	219	C20H18ClN5O2S	428.0	5.6	95	Ex. 35
79	230	C21H20ClN5O2S	442.4	6.5	100	Ex. 37
80	245	C21H20ClN5O2S	442.0	6.1	94	Ex. 35
81	254	C22H22ClN5O2S	456.1	6.9	95	Ex. 35
82	257	C21H23N5O2	378.2	4.3	100	Ex. 36
83	263	C20H21N5O2	364.2	10.0	96	Ex. 35
84	269	C21H18ClN5O2S	440.4	6.2	100	Ex. 37
85	280	C22H25N5O2	392.2	5.4	100	Ex. 35
86	287	C23H22ClN5O2S	468.0	7.1	95	Ex. 35
87	288	C22H21ClN4O2S2	472.9	11.8	97	Ex. 35
88	297	C23H27N5O2	406.2	12.9	98	Ex. 35
89	303	C24H24ClN5O2S	482.4	8.8	100	Ex. 37
90	321	C19H13ClF3N5O2S	468.4	7.3	99	Ex. 37
91	330	C23H21N5O2	400.5	5.0	99	Ex. 35
92	347	C25H18ClFN4OS2	509.4	15.0	99	Ex. 37
93	348	C24H17ClFN5O2S	494.2	8.0	100	Ex. 37
94	361	C26H20ClN5O4S	534.0	9.4	78	Ex. 35
95	370	C20H13BrClF3N4O3S	563.1	10.4	100	Ex. 35
96	492	C23H23ClN6O2S	483.1	10.8	93	Ex. 33
97	504	C24H25ClN6O2S	497.5	8.6	84	Ex. 33
98	536	C30H27ClN6O3S	587.4	9.0	79	Ex. 33
99	595	C21H25N5O2	380.2	5.2	100	Ex. 35
100	596	C22H22ClN5O2S	456.1	6.9	98	Ex. 35
101	601	C21H25N5O2	380.2	5.3	100	Ex. 35
102	602	C22H22ClN5O2S	456.1	7.1	94	Ex. 35
103	605	C22H29N5O2	396.3	5.1	100	Ex. 35
104	615	C22H27N5O2	394.1	7.5	99	Ex. 35
105	616	C21H26N4O3	383.2	10.3	78	Ex. 28
106	617	C21H26N4O2S	399.1	11.6	87	Ex. 35
107	618	C20H26N6O2	383.2	8.1	60	Ex. 28
108	627	C22H23ClN4O3S	459.3	15.0	95	Ex. 35
109	628	C22H23ClN4O2S2	475.2	15.7	100	Ex. 35
110	634	C22H27N5O2	394.2	5.7	100	Ex. 53
111	641	C23H27N5O2	406.2	5.9	100	Ex. 35
112	646	C24H24ClN5O2S	482.0	6.9	95	Ex. 35
113	657	C21H23N5O2	378.3	4.3	97	Ex. 35
114	659	C22H20ClN5O2S	454.1	6.5	94	Ex. 35
115	664	C23H24ClN5O2S	470.2	9.1	99	Ex. 35
116	667	C24H29N5O2	420.2	6.3	100	Ex. 36
117	668	C25H26ClN5O2S	496.0	8.3 8.5	80	Ex. 36
118	668	C25H26ClN5O2S	496.0	8.3	89	Ex. 36
119	673	C25H26ClN5O3S	512.0	6.6	98	Ex. 36
				6.9
120	678	C28H32ClN5O2S	538.1	11.1	97	Ex. 36
121	689	C25H25ClN6O3S	525.0	5.9	78	Ex. 36
122	694	C24H29N5O2	420.2	6.6	100	Ex. 35
123	696	C25H26ClN5O2S	496.0	8.5	98	Ex. 35
124	702	C19H21N5O3	368.2	9.5	82	Ex. 35
125	704	C20H18ClN5O3S	444.0	5.4	87	Ex. 35
126	709	C21H21ClN6O2S	457.1	4.8	94	Ex. 35
127	713	C21H19ClN6O3S	471.0	5.2	85	Ex. 36
128	718	C22H20ClN5O4S	486.0	6.0	90	Ex. 35
129	723	C24H23N5O2	414.5	5.0	98	Ex. 35
130	724	C25H20ClN5O2S	490.4	8.1	100	Ex. 37
131	729	C25H20ClN5O3S	506.0	8.0	90	Ex. 35
132	733	C25H25N5O2	428.0	6.7	98	Ex. 35
133	734	C26H22ClN5O2S	504.0	8.5	94	Ex. 35
134	741	C22H20ClN5O2S	454.0	5.7	87	Ex. 35
135	760	C20H24N6O2	381.1	5.1	98	Ex. 32
136	768	C21H21ClN6O2S	457.1	5.4	95	Ex. 32
137	770	C20H20ClN5O2S2	461.9	10.9	99	Ex. 32
138	776	C24H25ClN6O2S	497.0	7.7	95	Ex. 32
139	785	C23H22N6O2	415.0	6.9	96	Ex. 32
140	795	C23H18ClN5O2S2	495.9	12.1	99	Ex. 32
141	801	C24H18ClFN6O2S	508.9	7.9	97	Ex. 32
142	802	C24H18ClFN6O2S	508.9	8.1	85	Ex. 32
143	803	C24H18Cl2N6O2S	526.9	9.1	95	Ex. 32
144	804	C25H21ClN6O3S	520.9	7.7	98	Ex. 32
145	805	C25H21ClN6O2S	504.9	7.9	95	Ex. 32
146	806	C25H21ClN6O2S	504.9	8.2	85	Ex. 32
147	807	C25H21ClN6O2S	504.9	8.1	89	Ex. 32
148	808	C24H18Cl2N6O2S	520.8	9.3	97	Ex. 32
149	809	C24H18Cl2N6O2S	526.9	8.7	96	Ex. 32
150	810	C24H18ClFN6O2S	508.9	7.7	96	Ex. 32
151	811	C25H21ClN6O3S	520.9	8.9	93	Ex. 32
152	812	C25H21ClN6O3S	520.9	7.4	99	Ex. 32
153	912	C22H26N4O3	349.5	9.5	91	Ex. 28
154	915	C21H25N5O3	396.3	5.5	98	Ex. 28
155	917	C20H24N4O4	385.3	10.9	66	Ex. 28
156	918	C20H24N4O3S	401.5	12.4	93	Ex. 28
157	948	C18H21ClN4O3S	409.2	11.4	82	Ex. 26
158	956	C24H25ClN4O3S	485.2	13.9	91	Ex. 26
159	968	C23H29ClN4O3S	477.3	12.9	95	Ex. 28
160	970	C19H19ClN4O3S	419.3	10.9	98	Ex. 27
161	972	C23H27ClN4O3S	475.2	11.4	83	Ex. 27
162	973	C25H30ClN5O3S	499.2	7.7	81	Ex. 27
163	974	C25H23ClN4O3S	495.5	10.9	98	Ex. 27
164	975	C25H22ClFN4O3S	513.2	11.1	95	Ex. 27
165	976	C26H25ClN4O4S	525.2	11.0	98	Ex. 27
166	977	C25H24ClN5O3S	510.2	7.9	28	Ex. 27
167	978	C25H22Cl2N4O3S	529.2	11.5	95	Ex. 27
168	979	C24H22ClN5O3S	496.2	7.9	72	Ex. 27
169	980	C24H30ClN5O3S	487.3	7.5	92	Ex. 27
170	982	C22H27ClN4O3SSi	491.4	12.0	87	Ex. 27
171	983	C23H23ClN4O3S	471.3	10.5	92	Ex. 28
172	984	C23H22ClFN4O3S	489.2	10.9	85	Ex. 28
173	985	C24H22ClF3N4O3S	539.2	12.1	92	Ex. 28
174	986	C24H22ClF3N4O4S	555.3	12.2	93	Ex. 28
175	987	C23H22Cl2N4O3S	505.1	11.6	95	Ex. 28
176	988	C25H25ClN4O4S	513.3	9.8	88	Ex. 28
177	989	C29H27ClN4O4S	563.3	12.5	91	Ex. 28
178	990	C25H27ClN4O5S	531.3	9.5	91	Ex. 28
179	991	C25H28ClN5O3S	514.2	7.3	79	Ex. 28
180	992	C24H25ClN4O3S	485.3	11.1	94	Ex. 28
181	993	C27H25ClN4O3S	521.6	—	81	Ex. 28
182	994	C25H27ClN4O3S	499.2	11.6	96	Ex. 28
183	995	C21H21ClN6O3S	473.2	8.0	22	Ex. 28
184	996	C26H28ClN5O4S	542.3	8.7	90	Ex. 28
185	997	C29H33ClN4O3S	553.3	14.0	88	Ex. 28
186	998	C22H22ClN5O3S	472.2	6.6	78	Ex. 28
187	999	C22H22ClN5O3S	472.4	8.0	97	Ex. 28
188	1001	C21H21ClN4O4S	461.1	12.5	84	Ex. 28
189	1002	C21H21ClN4O3S2	477.1	13.1	94	Ex. 28
190	1003	C23H24ClN5O4S	502.0	11.1	61	Ex. 28
191	1004	C23H24ClN5O4S	502.0	11.5	71	Ex. 28
192	1005	C23H24ClN5O4S	502.1	7.7	93	Ex. 28
193	1006	C22H21Cl2N5O3S	506.0	12.8	90	Ex. 28
194	1007	C22H21ClFN5O3S	490.1	12.1	80	Ex. 28
195	1008	C22H21ClFN5O3S	490.1	12.8	94	Ex. 28
196	1009	C26H24ClN5O3S	522.0	10.4	54	Ex. 28
197	1010	C24H22ClN5O3S	496.4	14.7	88	Ex. 28
198	1011	C23H22ClFN4O3S	489.3	13.0	99	Ex. 28
199	1012	C23H22ClFN4O3S	489.4	13.3	96	Ex. 28
200	1013	C22H23ClN4O3S2	491.3	12.9	99	Ex. 28
201	1014	C20H21ClN6O3S	461.4	8.9	98	Ex. 28
202	1106	C18H19N5O2	338.4	5.1	97	Ex. 40
203	1131	C15H15N5O2	298.3	2.2	99	Ex. 40
204	1132	C14H13N5O2	284.2	1.7	99	Ex. 40
205	1146	C16H15N5O2	310.4	2.6	99	Ex. 40
206	1161	C19H15N5O2	346.2	5.9	96	Ex. 40
207	1168	C19H23N5O2	354.3	7.1	99	Ex. 40
208	1170	C15H14N4O3	299.2	4.4	96	Ex. 39
209	1174	C12H10N4O	227.2	2.4	100	Ex. 28
210	1175	C12H9ClN4O	261.1	4.4	95	Ex. 41
211	1177	C11H8N4O	213.1	5.0	99	Ex. 28
212	1179	C18H14N4O	303.2	7.2	99	Ex. 39
213	1181	C19H15N7O	358.1	3.6	100	Ex. 38
214	1182	C23H16ClN7OS	474.0	6.8	67	Ex. 38
215	1183	C22H17ClN8OS	477.1	7.7	100	Ex. 38
216	1184	C23H19N7O	410.3	2.3	100	Ex. 38
217	1185	C24H18ClN7OS	487.9	6.0	90	Ex. 38
218	1186	C22H17ClF3N7OS	520.1	8.1	100	Ex. 38
219	1206	C20H19ClN6O2S	443.1	6.7	97	Ex. 35
220	1216	C21H21ClN6O2S	457.0	8.6	87	Ex. 8
221	1217	C22H23ClN6O2S	471.1	7.6	83	Ex. 35
222	1228	C23H25ClN6O2S	485.2	8.2	96	Ex. 35
223	1236	C25H26ClN5O2S	497.9	8.4	96	Ex. 36
224	1237	C24H27ClN6O2S	499.2	8.5	99	Ex. 36
225	1243	C25H22ClFN6O2S	525.2	8.5	95	Ex. 35
226	1250	C21H23ClN6O2S	459.2	7.5	95	Ex. 35
227	1257	C21H23ClN6O2S	459.2	7.6	98	Ex. 35
228	1258	C18H24N6O2	357.2	5.9	100	Ex. 53
229	1259	C18H23ClN6O2	391.2	6.7	98	Ex. 50
230	1260	C21H27N5O2	382.2	5.3	100	Ex. 53
231	1261	C20H28N6O2	385.3	6.4	96	Ex. 35
232	1262	C21H30N6O2	399.3	6.6	100	Ex. 35
233	1271	C21H28N6O2	397.2	5.8	100	Ex. 35
234	1277	C23H28N6O3	437.3	7.6	79	Ex. 53
235	1278	C22H26N6O3	423.2	7.2	100	Ex. 53
236	1282	C23H25N5O2S	436.2	6.0	95	Ex. 53
237	1284	C22H26N6O2S	439.2	7.5	100	Ex. 53
238	1286	C23H28N6O2S	453.2	8.0	100	Ex. 53
239	1287	C23H24ClN5O3S	486.3	6.7	100	Ex. 67
240	1288	C22H25ClN6O2S	473.1	7.8	93	Ex. 35
241	1293	C23H27ClN6O2S	487.1	8.6	100	Ex. 28
242	1296	C23H28N6O2S	453.2	8.1	95	Ex. 53
243	1297	C21H25N5O2	380.2	5.2	96	Ex. 53
244	1331	C23H27N7O2	434.2	5.2	100	Ex. 53
245	1332	C22H28N8O2	437.3	5.9	100	Ex. 53
246	1333	C26H32N6O4	493.2	7.1	81	Ex. 53
247	1334	C25H28N6O4	477.2	7.5	100	Ex. 53
248	1335	C23H25N5O3	420.2	5.6	99	Ex. 53
249	1337	C22H26N6O3	423.2	7.1	100	Ex. 53
250	1338	C22H26N6O2S	439.2	7.6	98	Ex. 53
251	1341	C23H28N6O2S	453.2	8.3	100	Ex. 53
252	1364	C21H23N5O2	378.3	4.3	98	Ex. 35
253	1374	C21H21ClN6O2S	457.1	7.1	96	Ex. 35
254	1399	C23H25ClN6O2S	485.2	8.0	92	Ex. 36
255	1405	C24H29N5O2	420.2	6.1	100	Ex. 36
256	1413	C25H26ClN5O2S	497.9	8.7	96	Ex. 36
257	1415	C24H27ClN6O2S	499.1	8.6	100	Ex. 36
258	1423	C25H31N5O2	434.4	6.5	98	Ex. 36
259	1427	C25H29ClN6O2S	513.2	9.3	96	Ex. 36
260	1430	C21H21ClN6O2S	457.1	7.1	89	Ex. 35
261	1445	C24H27ClN6O2S	499.2	8.8	100	Ex. 36
262	1482	C25H31N5O2	434.4	6.8	96	Ex. 35
263	1486	C25H29ClN6O2S	513.2	9.5	100	Ex. 36
264	1490	C22H27N5O2	394.4	5.4	98	Ex. 35
265	1494	C22H25ClN6O2S	473.2	8.2	98	Ex. 35
266	1511	C26H23ClN6O2S	519.1	6.5	91	Ex. 33
267	1514	C21H19ClN6O2S	455.1	6.9	87	Ex. 35
268	1519	C20H23N5O2S	398.2	4.9	100	Ex. 36
269	1520	C21H20ClN5O2S2	474.0	5.3	98	Ex. 35
270	1522	C24H25ClN6O3S	513.1	4.2	100	Ex. 36
271	1530	C25H27ClN6O2S	512.9	5.4	92	Ex. 36
272	1533	C20H14ClF4N5O2S	500.0	6.3	65	Ex. 35
273	1535	C21H13ClF7N5O2S	568.0	7.7	96	Ex. 35
274	1549	C25H31N5O2	434.2	6.8	100	Ex. 35
275	1553	C25H29ClN6O2S	513.2	9.5	90	Ex. 35
276	1554	C26H33N5O2	448.2	7.5	100	Ex. 35
277	1558	C26H31ClN6O2S	527.2	10.3	95	Ex. 35
278	1566	C24H25ClN6O2S	497.2	8.3	97	Ex. 36
279	1589	C23H25F2N5O2	442.23	5.3	98	Ex. 36
280	1600	C23H23ClF2N6O2S	521.2	7.8	98	Ex. 36
281	1623	C27H35N5O2	462.2	7.5	100	Ex. 35
				7.7
282	1647	C24H26F3N5O2	474.2	6.2	79	Ex. 36
				6.5
283	1654	C24H24ClF3N6O2S	553.2	9.1	99	Ex. 36
284	1660	C25H31N5O2	434.3	6.5	99	Ex. 36
				6.6
285	1661	C25H29ClN6O2S	513.2	9.3	98	Ex. 36
				9.4
286	1673	C22H25N5O3	408.2	4.5	100	Ex. 36
287	1679	C22H23ClN6O3S	487.1	6.4	95	Ex. 36
288	1682	C28H31ClN6O4S	583.2	6.9	96	Ex. 36
289	1691	C28H31ClN6O4S	583.2	6.9	98	Ex. 36
290	1693	C27H32ClN7O4S	586.2	8.4	95	Ex. 36
291	1695	C27H32ClN7O4S	586.2	8.6	95	Ex. 36
292	1696	C28H31ClN6O4S	583.1	7.0	99	Ex. 36
293	1697	C27H32ClN7O4S	586.2	8.6	94	Ex. 36
294	1698	C26H30ClN7O4S	572.1	7.8	93	Ex. 36
295	1699	C27H29ClN6O4S	569.1	6.2	98	Ex. 36
296	1700	C26H30ClN7O4S	572.2	7.8	92	Ex. 36
297	1715	C29H33ClN6O3S	581.2	6.3	93	Ex. 36
298	1719	C27H27ClN6O3S	551.1	5.2	96	Ex. 36
299	1721	C28H29ClN6O3S	565.2	5.7	93	Ex. 36
300	1739	C27H31ClN6O2S	539.2	4.7	90	Ex. 36
301	1748	C28H33ClN6O2S	553.2	5.1	95	Ex. 36
302	1751	C28H33ClN6O2S	553.2	5.2	96	Ex. 36
303	1753	C29H35ClN6O2S	567.2	5.5	89	Ex. 36
304	1758	C27H29ClN6O2S	537.1	4.7	96	Ex. 36
305	1778	C25H22F3N5O2	482.3	6.5	99	Ex. 36
306	1804	C27H21ClN6O2S	530.9	7.4	92	Ex. 36
307	1805	C28H23ClN6O2S	543.1	8.1	89	Ex. 36
308	1806	C27H22ClN5O2S	516.1	6.8	96	Ex. 35
309	1808	C27H22ClN5O2S	518.0	8.1	90	Ex. 36
310	1823	C26H23ClN6O2S	519.1	5.2	94	Ex. 36
311	1828	C27H25ClN6O2S	533.1	5.2	89	Ex. 36
312	1833	C26H21ClN6O2S	517.1	5.9	86	Ex. 36
313	1843	C23H25N5O3	419.2	4.6	86	Ex. 36
314	1846	C26H27N5O2	441.2	6.1	90	Ex. 36
315	1849	C28H36N6O4	520.3	6.3	39	Ex. 36
316	1852	C29H38N6O4	534.3	6.9	43	Ex. 36
317	1855	C19H18F3N5O2	406.2	4.4	98	Ex. 36
318	1860	C19H16ClF3N6O2S	485.1	7.4	91	Ex. 36
319	1861	C18H16ClF2N5O2	408.2	4.9	36	Ex. 36
320	1865	C20H22ClN5O2	400.3	4.6	60	Ex. 35
321	1868	C21H23N5O2	378.3	4.4	97	Ex. 35
322	1885	C20H20F3N5O2	420.1	5.0	100	Ex. 36
323	1890	C20H18ClF3N6O2S	499.1	7.7	98	Ex. 36
324	1891	C24H29N5O2	420.2	6.3	100	Ex. 36
325	1894	C24H27ClN6O2S	499.2	9.0	100	Ex. 35
326	1899	C21H22F3N5O2	434.1	5.5	100	Ex. 36
327	1900	C21H20ClF3N6O2S	513.1	8.2	98	Ex. 36
328	1913	C21H20N6O2	389.1	4.1	100	Ex. 36
329	1915	C21H21Cl2N5O2	446.1	5.5	100	Ex. 36
330	2003	C24H27ClN6O2	467.2	8.6	70	Ex. 53
331	2004	C26H25N5O2	440.5	6.0	99	Ex. 35
332	2005	C22H23ClN6O2S	471.0	7.2	97	Ex. 32
333	2006	C23H23ClN6O2S	483.0	7.4	97	Ex. 32
334	2007	C24H21F3N6O2	483.3	7.0	99	Ex. 32
335	2008	C24H21F3N6O3	499.3	7.1	96	Ex. 32
336	2009	C23H17Cl2N7O2S	526.0	6.5	90	Ex. 33
337	2010	C25H20ClFN6O2S	523.1	6.3	97	Ex. 32
338	2011	C24H21ClFN7O2S	526.1	7.9	97	Ex. 32
339	2012	C24H20ClN7O2S	506.1	4.0	81	Ex. 33
340	2013	C25H23F3N6O3	513.1	6.8	100	Ex. 32
341	2014	C25H27ClN6O2S	511.0	9.4	97	Ex. 32
342	2015	C24H28ClN7O2S	514.1	8.5	100	Ex. 32
343	2016	C25H21ClN6O2S	505.0	7.7	93	Ex. 32
344	2017	C24H21F3N6O2	483.2	6.8	100	Ex. 32
345	2018	C24H21F3N6O2	483.3	6.0	99	Ex. 32
346	2019	C24H26ClN7O3S	528.1	4.4	96	Ex. 33
347	2020	C25H28ClN7O3S	542.1	4.3	100	Ex. 33
348	2021	C25H28ClN7O2S	526.1	4.8	98	Ex. 33
349	2022	C25H32N6O2	449.2	6.7	100	Ex. 32
350	2023	C26H29ClN6O2S	525.1	7.3	98	Ex. 32
351	2024	C25H30ClN7O2S	528.1	8.8	98	Ex. 33
352	2025	C26H29ClN6O2S	525.2	7.2	94	Ex. 33
353	2026	C25H30ClN7O2S	528.1	8.9	100	Ex. 32
354	2027	C25H27ClN6O3S	527.2	5.5	96	Ex. 33
355	2028	C28H29ClN6O2S	549.0	9.7	97	Ex. 32
356	2029	C25H20ClFN6O2S	523.1	5.8	97	Ex. 32
357	2031	C24H23FN6O2	447.1	5.5	100	Ex. 32
358	2032	C25H20ClFN6O2S	523.1	6.3	98	Ex. 32
359	2033	C24H21ClFN7O2S	526.1	7.8	94	Ex. 32
360	2034	C25H19ClF2N6O2S	541.0	6.7	96	Ex. 32
361	2036	C24H20ClF2N7O2S	544.1	7.6	94	Ex. 32
362	2040	C24H22Cl2N6O2	497.3	6.6	100	Ex. 33
363	2042	C25H23F3N6O2	497.3	6.3	97	Ex. 33
364	2046	C25H23F3N6O2	497.3	6.6	98	Ex. 33
365	2049	C25H21ClF3N7O2S	576.1	8.9	100	Ex. 32
366	2052	C26H20ClF3N6O3S	589.0	7.6	98	Ex. 32
367	2053	C25H21ClF3N7O3S	592.1	9.0	100	Ex. 32
368	2054	C24H24F3N7O3	516.2	8.0	100	Ex. 32
369	2056	C26H20ClF3N6O3S	589.0	7.7	98	Ex. 32
370	2058	C25H21ClF3N7O3S	592.1	9.1	100	Ex. 32
371	2060	C26H23ClN6O3S	535.1	6.3	99	Ex. 32
372	2062	C26H23ClN6O3S	535.1	6.2	96	Ex. 32
373	2063	C25H24ClN7O3S	538.1	7.7	91	Ex. 32
374	2064	C25H26N6O3	459.1	5.3	100	Ex. 32
375	2065	C26H23ClN6O3S	535.1	6.1	99	Ex. 32
376	2067	C25H24ClN7O3S	538.1	7.7	91	Ex. 32
377	2068	C27H25ClN6O4S	565.1	5.8	89	Ex. 32
378	2069	C26H26ClN7O4S	568.1	7.0	63	Ex. 32
379	2070	C27H25ClN6O4S	565.1	6.5	87	Ex. 32
380	2071	C26H26ClN7O4S	568.1	7.7	94	Ex. 32
381	2072	C26H21ClN6O4S	549.1	6.2	96	Ex. 32
382	2073	C25H22ClN7O4S	552.0	7.5	90	Ex. 32
383	2078	C26H23ClN6O4S2	583.0	5.6	78	Ex. 32
384	2080	C26H27ClN8O2S	551.0	5.8	95	Ex. 33
385	2081	C24H20ClN7O2S	506.1	4.1	65	Ex. 33
386	2083	C24H20ClN7O2S	506.1	4.1	75	Ex. 32
387	2085	C24H19Cl2N7O2S	540.0	5.0	88	Ex. 32
388	2086	C23H20Cl2N8O2S	543.0	6.9	100	Ex. 33
389	2087	C23H19ClN6O3S	495.6	5.6	90	Ex. 32
390	2089	C23H19ClN6O2S2	511.0	5.8	94	Ex. 32
391	2093	C26H23ClN6O2S	519.1	6.5	98	Ex. 32
392	2094	C26H23ClN6O2S	519.1	6.5	98	Ex. 32
393	2095	C27H25ClN6O3S	549.1	6.4	100	Ex. 32
394	2096	C27H25ClN6O3S	549.1	6.4	94	Ex. 32
395	2097	C26H26ClN7O3S	552.1	7.9	94	Ex. 32
396	2098	C25H23ClFN7O2S	540.1	8.2	100	Ex. 32
397	2099	C25H18ClF3N6O2S	558.9	9.6	96	Ex. 32
398	2100	C23H17Cl2N7O2S	526.0	6.0	93	Ex. 33
399	2101	C21H16ClN7O2S2	497.9	6.4	85	Ex. 32
400	2102	C24H20ClF2N7O2S	544.1	8.1	93	Ex. 33
401	2103	C25H22F4N6O2	515.3	6.7	97	Ex. 33
402	2105	C25H22F4N6O2	515.3	6.6	100	Ex. 33
403	2107	C30H28N6O2	505.4	7.0	80	Ex. 33
404	2109	C25H21ClN6O2S	505.1	6.1	89	Ex. 33
405	2110	C18H21N5O3	356.3	4.5	91	Ex. 28
406	2116	C20H26N6O3	399.1	6.7	100	Ex. 28
407	2119	C23H32N6O3	441.2	8.1	86	Ex. 28
408	2120	C19H22N4O4	371.0	7.4	33	Ex. 70
409	2122	C23H26N6O4	451.0	7.7	41	Ex. 70
410	2127	C18H19ClN8O3S	462.9	8.6	98	Ex. 28
411	2141	C26H28N4O4	461.0	11.5	99	Ex. 10
412	2142	C31H31N5O4	538.0	9.3	99	Ex. 28
413	2143	C30H32N6O4	541.1	11.4	70	Ex. 28
414	2146	C22H22ClN5O3S	472.1	6.8	99	Ex. 35
415	2147	C25H20ClN5O3S	506.1	7.1	98	Ex. 35
416	2148	C22H22ClN5O3S	472.1	6.8	99	Ex. 35
417	2158	C20H23N5O2	366.4	4.7	100	Ex. 49
418	2161	C24H29N5O2	420.3	7.1	93	Ex. 63
419	2162	C23H30N6O2	423.3	7.8	100	Ex. 63
420	2164	C24H28N6O2S	465.3	8.6	100	Ex. 53
421	2165	C29H33N5O4	516.4	7.5	99	Ex. 53
422	2165	C25H27N5O3	446.2	7.3	98.9	Ex. 53
423	2166	C28H34N6O4	519.3	8.1	100	Ex. 53
424	2170	C24H28N6O3	449.3	8.3	100	Ex. 53
425	2175	C30H31N5O3	510.3	7.6	88	Ex. 63
426	2176	C29H32N6O3	513.4	8.2	100	Ex. 63
427	2183	C24H24FN5O2S	466.3	6.2	98	Ex. 53
428	2184	C23H25FN6O2S	469.3	7.6	100	Ex. 53
429	2185	C28H30FN5O4	520.3	6.1	99	Ex. 53
430	2186	C27H31FN6O4	523.3	7.7	98	Ex. 53
431	2187	C24H24FN5O3	450.3	5.9	98	Ex. 53
432	2188	C23H25FN6O3	453.3	7.3	100	Ex. 53
433	2202	C21H25N5O2	380.4	5.3	100	Ex. 49
434	2209	C21H19N5O2	374.3	5.1	100	Ex. 49
435	2210	C24H22FN5O2	432.2	7.0	93	Ex. 63
436	2211	C23H23FN6O2	435.3	7.8	100	Ex. 63
437	2212	C25H22F3N5O2	482.3	7.2	79	Ex. 63
438	2224	C25H22F3N5O3	498.3	7.5	99	Ex. 63
439	2240	C25H24FN5O2	446.3	7.0	96	Ex. 63
440	2241	C24H25FN6O2	449.3	7.6	100	Ex. 63
441	2265	C25H31N5O2	434.3	7.5	98	Ex. 63
442	2266	C24H32N6O2	437.4	8.3	100	Ex. 63
443	2267	C26H29N5O2S	476.3	7.5	98	Ex. 53
444	2268	C25H30N6O2S	479.3	9.1	100	Ex. 53
445	2270	C29H31N5O4	514.0	8.2	100	Ex. 53
446	2271	C26H29N5O3	460.3	7.4	93	Ex. 53
447	2272	C25H30N6O3	463.3	8.8	100	Ex. 53
448	2275	C26H33N5O2	448.3	8.2	83	Ex. 63
449	2277	C25H34N6O2	451.4	9.0	100	Ex. 63
450	2281	C27H31N5O2S	490.4	7.7	100	Ex. 53
451	2282	C26H32N6O2S	493.3	9.8	100	Ex. 53
452	2287	C31H37N5O4	544.5	7.7	100	Ex. 53
453	2288	C29H36N6O4	533.3	9.0	100	Ex. 53
454	2288	C30H38N6O4	547.4	9.4	99	Ex. 53
455	2290	C27H31N5O3	474.5	7.5	100	Ex. 53
456	2291	C26H32N6O3	477.4	9.5	100	Ex. 53
457	2296	C25H25N5O2	428.3	5.9	96	Ex. 63
458	2298	C24H22FN5O2	432.3	5.8	95	Ex. 63
459	2299	C19H23N5O2	354.4	4.6	100	Ex. 49
460	2300	C18H19N5O4	370.3	2.2	100	Ex. 49
461	2301	C18H21N5O3	356.4	2.5	100	Ex. 49
462	2305	C25H24FN5O2	446.3	5.9	98	Ex. 63
463	2311	C26H24F3N5O2	496.3	7.1	98	Ex. 63
464	2325	C26H24F3N5O3	512.3	7.3	98	Ex. 63
465	2329	C26H27N5O2	442.4	6.3	98	Ex. 63
466	2336	C27H25N5O2S	484.3	7.3	98	Ex. 53
467	2337	C26H26N6O2S	487.3	8.7	100	Ex. 53
468	2340	C24H26N6O2	431.4	7.4	100	Ex. 53
469	2341	C26H27N5O2	442.5	6.4	100	Ex. 53
				6.6
470	2342	C31H29N5O2	504.4	7.7	100	Ex. 53
				7.9
471	2343	C32H29N5O3	532.4	8.0	100	Ex. 53
472	2344	C31H31N5O4	538.5	6.9	100	Ex. 53
473	2347	C27H25N5O3	468.3	7.1	98	Ex. 53
474	2348	C26H26N6O3	471.3	8.4	100	Ex. 53
475	2350	C23H23N5O3	418.3	5.1	98	Ex. 63
476	2356	C26H27N5O2	442.2	7.1	87	Ex. 63
477	2357	C25H28N6O2	445.3	7.8	100	Ex. 63
478	2446	C17H11ClN4O	323.2	4.5	100	Ex. 53
479	2448	C17H12N4O2	305.3	2.5	100	Ex. 53
480	2452	C18H14N4O2	319.3	4.2	100	Ex. 53
481	2459	C18H14N4O2	319.3	2.9	100	Ex. 53
482	2469	C16H13N5O	292.2	2.9	100	Ex. 53
483	2471	C15H10N4OS	295.3	3.2	100	Ex. 53
484	2481	C15H10N4O2	279.3	2.5	100	Ex. 53
485	2484	C17H10Cl2N4O	357.0	5.5	100	Ex. 53
486	2486	C19H16N4O3	349.2	4.1	100	Ex. 53
487	2490	C18H15N5O3S	382.3	4.0	100	Ex. 53
488	2492	C18H12N4O3	333.3	2.7	100	Ex. 53
489	2495	C19H13N5O	328.3	5.1	100	Ex. 53
490	2500	C26H22N4O3	439.0	7.5	94	Ex. 53
491	1562	C24H27N5O2	418.5	5.7	99	Ex. 36
492	1895	C25H28N6O2	445.5	5.7	99	Ex. 36
493	1875	C21H19F6N5O2	488.3	6.5	99	Ex. 36
494	2514	C30H31N5O3	510.5	6.6	99	Ex. 36

Example 495

¹H-NMR(400 MHz, DMSO-d₆ or CDCl₃) of the compounds according to the present invention were measured. Data of chemical shift values (δ: ppm) and coupling constant (J: Hz) are shown in Table 3. Compound numbers in Table 3 designate compounds in Table 1 listed as preferred specific examples, and example numbers in the table denote examples of corresponding synthesized compounds

Ex.	Compound
no.	no.	NMR data δ(ppm)	Solvent
72	27	1.28-1.44(m, 2H), 1.76(m, 2H), 2.76(m, 1H),	DMSO-d6
		2.84-3.01(m, 2H), 3.15(m, 1H), 3.68(m, 1H), 3.87(d,
		J=12.96, 1H), 4.39(d, J=11.96, 1H), 4.62(m, 2H),
		7.52(m, 2H), 7.63(m, 1H), 7.79(dd, J=5.38,
		J=8.06, 1H), 7.97(m, 3H), 8.24(s, 1H), 8.59(d, J=5.36,
		1H), 8.78(d, J=8.32, 1H), 9.37(s, 1H),
		12.24(brs, 1H).
73	29	0.00(m, 2H), 0.25(m, 2H), 2.28(m, 1H), 2.37(t, J=6.70,	DMSO-d6
		2H), 4.34(t, J=6.60, 2H), 7.58(dd, J=5.50,
		J=7.94, 1H), 7.69(d, J=3.92, 1H), 7.73(s, 1H),
		7.86(s, 1H), 8.35(d, J=5.36, 1H), 8.58(d, J=8.28,
		1H), 9.14(s, 1H), 12.02(brs, 1H).
75	80	3.96(m, 2H), 4.49(m, 1H), 4.88(m, 1H), 7.11(m,	DMSO-d6
		1H), 7.73-7.79(m, 2H), 7.83(m, 1H), 7.88(brs,
		1H), 8.03(t, J=7.7, 1H), 8.18(d, J=8.5, 1H),
		8.64(s, 1H), 10.00(brs, 1H), 12.29(brs, 1H).
202	1106	1.44(brs, 2H), 1.62(brs, 4H), 3.45(m, 4H),	DMSO-d6
		5.39(s, 2H), 7.81(dd, J=5.48, J=8.16, 1H), 7.98(s, 1H),
		8.09(s, 1H), 8.60(d, J=5.40, 1H), 8.80(d, J=8.04,
		1H), 9.39(s, 1H), 12.18(brs, 1H).
206	1161	5.36(s, 2H), 7.05(m, 1H), 7.31(t, J=7.56, 2H),	DMSO-d6
		7.58(d, J=7.56, 2H), 7.81(dd, J=5.24, J=8.16,
		1H), 8.00(s, 1H), 8.18(s, 1H), 8.61(d, J=5.36,
		1H), 8.80(d, J=8.04, 1H), 9.41(s, 1H), 10.37(s,
		1H), 12.26(brs, 1H).
208	1170	1.19-1.23(m, 3H), 4.13-4.20(m, 2H), 5.30(s, 2H),	DMSO-d6
		7.79(m, 1H), 8.00(d, J=3.92, 1H), 8.15(d, J=4.16,
		1H), 8.60(m, 1H), 8.76(d, J=8.07, 1H), 9.37(s,
		1H), 12.28(brs, 1H).
209	1174	4.06(s, 3H), 7.84(dd, J=5.36, J=8.03, 1H),	DMSO-d6
		7.96(s, 1H), 8.16(s, 1H), 8.61(d, J=5.12, 1H),
		8.84(d, J=7.75, 1H), 9.39(s, 1H), 12.21(brs, 1H).
212	1179	5.67(s, 2H), 7.13-7.36(m, 5H), 7.80(dd, J=5.35,	DMSO-d6
		J=8.03, 1H), 8.00(s, 1H), 8.36(s, 1H), 8.60(d,
		J=5.36, 1H), 8.83(d, J=8.07, 1H), 9.40(s, 1H),
		12.29(brs, 1H).

Example 496

Determination of Inhibition of GSK-3 Activity

The reaction was initiated by adding 25 μL of phospho-glycogen synthase peptide-2 substrate solution [containing 6 μM phospho-glycogen synthase peptide-2, 20 μM ATP, 16 mM MOPS buffer (pH 7.0), 0.2 mM EDTA, 20 mM magnesium acetate, 0.1 μ Ci[γ-³³P]ATP (relative activity: approximately 110 TBq/mmol)] to 5 μL of each test compound using 5% dimethylsulfoxide as a solvent, and further adding 20 μL of GSK-3β enzyme solution [containing 10 mU recombinant human GSK-3β, 20 mM MOPS buffer (pH 7.0), 1 mM EDTA, 0.1% polyoxyethylene lauryl ether(23 Lauryl Ether; Brij 35), 5% glycerol, and 0.1% β-mercaptoethanol. After 20 minutes at room temperature, the reaction was terminated by the addition of the equivalent amount of 200 mM phosphoric acid solution. 90 μL of the reaction product was spotted onto a multiscreen PH plate (manufactured by Millipore) and washed with 100 mM phosphoric acid solution. The plate was dried, and 30 μL of MicroScint-O (manufactured by Packard BioScience) was added thereto. To evaluate inhibitory activity, cpm was counted using a scintillation counter. Here, Phospho GS Peptide 2 is an amino acid peptide having the following sequence: Tyr-Arg-Arg-Ala-Ala-Val-Pro-Pro-Ser-Pro-Ser-Leu-Ser-Arg-His-Ser-Ser-Pro-His-Gln-Ser(P)-Glu-Asp-Glu-Glu-Glu.

GSK-3 inhibitor activity values (IC₅₀ values) of the compounds according to the present invention were measured by the method described above. As a result, an inhibition activity of IC₅₀<100 nM was confirmed in compounds of compound numbers 263, 280, 287, 297, 615, 617, 618, 627, 629, 641, 668, 760, 785, 1014, 1183, 1206, 1216, 1217, 1228, 1237, 1243, 1250, 1257, 1271, 1286, 1287, 1288, 1293, 1296, 1374, 1399, 1405, 1415, 1423, 1427, 1430, 1445, 1494, 1514, 1549, 1553, 1566, 1589, 1600, 1647, 1654, 1660, 1661, 1679, 1693, 1695, 1715, 1721, 1890, 1900, 2007, 2008, 2010, 2011, 2012, 2013, 2014, 2015, 2017, 2022, 2026, 2031, 2032, 2033, 2034, 2036, 2040, 2042, 2046, 2049, 2053, 2054, 2058, 2062, 2063, 2064, 2065, 2067, 2068, 2069, 2070, 2071, 2072, 2073, 2078, 2080, 2083, 2085, 2086, 2095, 2097, 2098, 2102, 2103, 2105, 2107, 2212, 2224, 2311.

Also, an inhibition activity of 20 nM<IC₅₀<100 nM was confirmed in compounds of compound numbers 40, 217, 219, 230, 245, 269, 288, 303, 595, 596, 601, 602, 616, 626, 628, 634, 646, 657, 659, 664, 667, 668, 673, 689, 694, 696, 723, 733, 734, 741, 768, 770, 776, 793, 795, 801, 802, 803, 804, 805, 806, 807, 809, 810, 812, 915, 1182, 1186, 1236, 1260, 1277, 1278, 1282, 1284, 1335, 1337, 1338, 1341, 1364, 1413, 1482, 1486, 1490, 1519, 1520, 1533, 1554, 1558, 1623, 1673, 1682, 1691, 1696, 1700, 1719, 1739, 1748, 1751, 1753, 1758, 1778, 1806, 1808, 1846, 1849, 1852, 1855, 1865, 1868, 1885, 1894, 1899, 2004, 2005, 2006, 2016, 2018, 2019, 2020, 2021, 2024, 2025, 2027, 2029, 2052, 2056, 2060, 2081, 2087, 2089, 2094, 2099, 2100, 2101, 2146, 2147, 2148, 2161, 2175, 2183, 2184, 2210, 2211, 2240, 2241, 2265, 2266, 2275, 2296, 2298, 2305, 2325, 2329, 2331, 2332, 2336, 2337, 2341, 2342, 2347, 2348, 2350, 2448, 2486, 2492.

Also, an inhibition activity of 100 nM<IC₅₀<1 μM was confirmed in compounds of compound numbers 81, 84, 254, 257, 320, 321, 330, 348, 361, 492, 504, 536, 550, 605, 678, 684, 702, 704, 709, 713, 718, 724, 729, 808, 811, 917, 918, 946, 1001, 1002, 1007, 1008, 1178, 1181, 1184, 1185, 1258, 1259, 1261, 1262, 1297, 1331, 1333, 1334, 1511, 1522, 1530, 1535, 1697, 1804, 1805, 1823, 1833, 1843, 1860, 1861, 1891, 1913, 1915, 2003, 2023, 2028, 2093, 2096, 2109, 2116, 2158, 2162, 2164, 2165, 2166, 2170, 2176, 2186, 2187, 2188, 2202, 2209, 2264, 2267, 2268, 2269, 2270, 2271, 2272, 2277, 2281, 2282, 2288, 2290, 2291, 2292, 2299, 2300, 2340, 2344, 2345, 2356, 2357, 2445, 2446, 2452, 2459, 2469, 2471, 2481, 2484, 2490, 2495.

Compound numbers designate compounds in Table 1 listed as preferred specific examples.

As described above, the pyrrolopyrimidine derivatives according to the present invention exhibit strong inhibitory activity against GSK-3. Therefore, the pyrrolopyrimidine derivatives according to the present invention have been found to be inhibitors of GSK-3 activity to be used in prevention and/or treatment of various diseases associated with GSK-3, which are clinically applicable compounds.

Example 493

Preparation of Tablets

Tablets each comprising the following ingredients were prepared.

Compound (Example 1) 50 mg
Lactose              230 mg
Potato starch        80 mg
Polyvinylpyrrolidone 11 mg
Magnesium stearate   5 mg

The compound of the present invention (the compound prepared in Example 1), lactose, and potato starch were mixed, homogenously wetted with 20% ethanol solution of polyvinylpyrrolidone, passed through a 20 mesh sieve, dried at 45° C., and passed through again a 15 mesh sieve to obtain granules. The thus obtained granules were mixed with magnesium stearate and compressed into tablets.

Reference Example 15

Synthesis of N-{2-[4-chloro-6-(3-chloro(2-thienyl))-7-iodopyrrolo[3,2-d]pyrimidin-5-yl] -ethyl}-2,2,2-trifluoroacetoamide

A phosphorus oxychloride (3.0 mL) solution of N-{2-[6-(3-chloro(2-thienyl))-7-iodo-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}-2,2,2-trifluoroacetoamide (333 mg) was stirred at 110° C. for 2 hours. The reaction mixture was cooled to room temperature, and excess phosphorus oxychloride was distilled off under reduced pressure. A residue was dried in vacuo to obtain a crude product of the title compound as a brown oily compound. The product was not purified, but used for the following reaction. The ESI/MS data of the compound is given below.

ESI/MS m/e: 535.2(M⁺+H, C₁₄H₈Cl₂F₃IN₄OS)

Reference Example 16

Synthesis of N-{2-[7-bromo-4-chloro-6-(3-chloro(2-thienyl))pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-2,2,2-trifluoroacetoamide

A crude product of the title compound was obtained by using N-{2-[7-promo-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}-2,2,2-trifluoroacetoamide (333 mg) in a similar manner to that in Reference Example 15. The ESI/MS data of the compound is given below.

ESI/MS m/e: 489.0(M⁺+H, C₁₄H₈BrCl₂F₃N₄OS)

Reference Example 17

Synthesis of N-{2-[4,7-dichloro-6-(3-chloro(2-thienyl))pyrrolo [3,2-d]pyrimidin-5-yl]ethyl}-2,2,2-trifluoroacetoamide

A crude product of the title compound was obtained by using N-{2-[7-chloro-6-(3-chloro(2-thienyl))-4-oxo(3-hydropyrrolo[3,2-d]pyrimidin-5-yl)]ethyl}-2,2,2-trifluoroacetoamide (333 mg) in a similar manner to that in Reference Example 15. The ESI/MS data of the compound is given below.

ESI/MS m/e: 443.4(M⁺+H, C₁₄H₈Cl₃F₃N₄OS)

INDUSTRIAL APPLICABILITY

The pyrrolopyrimidinone derivatives of Formula (I) according to the present invention and its pharmaceutically acceptable salts have GSK-3 inhibitory activity and are used as effective ingredients of pharmaceutical products. Therefore, pharmaceutical agents containing these compounds as effective ingredients are expected as promising therapeutic drugs or preventive drugs in GSK-3 mediated diseases including diabetes, diabetic complications, Alzheimer's disease, neurodegenerative diseases manic depression, traumatic cerebrospinal injury, alopecia, inflammatory diseases, cancer and immunodeficiency.

Claims

1. A compound represented by the formula (I) or its pharmaceutically acceptable salts:

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein A1 represents a divalent acyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms.

3. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein A1 is —(CH2)2— or (CH2)3—.

4. The compound or a pharmaceutically acceptable salt thereof according to claim 2 or 3, wherein A2 represents a group other than a single bond.

5. The compound or a pharmaceutically acceptable salt thereof according to claim 2 or 3, wherein A2 represents —C(═O)—, —C(═O)—O—, —C(═O)—NH—, —C(═O)—NMe-, —NH—, —NH—C(═O)—, —NH—C(═O)—O—, —NH—C(═O)—NH—, —NH—C(═O)—NMe-, or —NH—C(═S)—.

6. The compound or a pharmaceutically acceptable salt thereof according to claim 2 or 3, wherein A2 represents —C(═O)—NH—, —NH—, —NH—C(═O)—, —NH—C(═O)—O—, or —NH—C(═O)—NH—.

7. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein both of A1 and A2 represent a single bond.

8. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein combination of G1, A3, A4, and G2 is any of the combinations of 1 to 10 in the following table.

9. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein G1 represents a group other than a single bond, A3 and A4 represent a single bond, and G2 represents a hydrogen atom.

10. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein G1 and A4 represent a single bond, A3 represents a group other than a single bond, and G2 represents a hydrogen atom.

11. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein G1 represents a group other than a single bond, A3 and A4 represent a single bond, and G2 represents a group other than a hydrogen atom.

12. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein G1 and A4 represent a single bond, A3 represents a group other than a single bond, and G2 represents a group other than a hydrogen atom.

13. The compound or a pharmaceutically acceptable salt thereof according to claim 12, wherein A3 represent an alkylene group having 1 to 3 carbon atoms.

14. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein G1 and A4 represent a group other than a single bond, A3 represents a single bond, and G2 represents a group other than a hydrogen atom.

15. The compound or a pharmaceutically acceptable salt thereof according to claim 14, wherein A4 represents —C(═O)—, —C(═O)—NH—, —O—, or —NH—C(═O)—.

16. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein G1 represents a single bond, A3 and A4 represent a group other than a single bond, and G2 represents a group other than a hydrogen atom.

17. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein G1 and A3 represent a group other than a single bond, A4 represents a single bond, and G2 represents a group other than a hydrogen atom.

18. The compound or a pharmaceutically acceptable salt thereof according to claim 17, wherein A3 represent an alkylene group having 1 to 3 carbon atoms.

19. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein G1, A3 and A4 represent a group other than a single bond, and G2 represents a group other than a hydrogen atom.

20. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein A4 represents —O—.

21. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein G1, A3 and A4 represent a group other than a single bond, and G2 represents a hydrogen atom.

22. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein G1, A3 and A4 represent a single bond, and G2 represents a hydrogen atom.

23. The compound or a pharmaceutically acceptable salt thereof according to claim 3, wherein A2 represents —NH—(C═O)— or —NH—(C═O)—NH—, G1 represents a single bond, and A3 represents a divalent acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms.

24. The compound or a pharmaceutically acceptable salt thereof according to claim 3, wherein A2 represents —NH—(C═O)—, —NH—(C═O)—NH—, —NH—, or —C(═O)—NH—, and G1 represents a group other than a single bond.

25. The compound or a pharmaceutically acceptable salt thereof according to claim 2 or 3, wherein A2 represents a single bond, and G1 represents an optionally substituted heterocyclic group, with the proviso that when the heterocyclic group of G1 is 5 or 6 membered monocyclic ring, then the 5 or 6 membered monocyclic heterocyclic group of G1 is substituted or the A3-G2 portion represents those other than a hydrogen atom.

26. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 4 to 6, wherein G1 represents an optionally substituted aromatic hydrocarbon group, an optionally substituted alicyclic hydrocarbon group having 7 to 10 carbon atoms, or an optionally substituted heterocyclic group, with the proviso that when the aromatic hydrocarbon group of G1 is a phenyl group, or the heterocyclic group of G1 is 5 or 6 membered monocyclic ring, then the phenyl group or the 5 or 6 membered monocyclic heterocyclic group of G1 is substituted, or the A3-G2 portion represents those other than a hydrogen atom.

27. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 4 to 6, wherein G1 and A4 represent a single bond, A3 represents an optionally substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms, G2 represents an optionally substituted alicyclic hydrocarbon group having 5 to 10 carbon atoms, an optionally substituted aromatic hydrocarbon group, or an optionally substituted heterocyclic group.

28. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 4 to 6, wherein G1 represents a single bond, A3 represents an optionally substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms, and A4 represents —C(═O)—, —C(═O)—NR121—, —C(═S)—NR122—, —C(═NR123)—, —O—C(O)—, —NR125—C(═O)—, —NR126—S(═O)2—, —NR127—C(═O)—O—, —NR128—C(═O)—NR129—, —NR130—C(═S)—, —NR131—C(═S)—NR132—, —S—, —S(═O)—, —S(═O)2—, —S(═O)2—NR133—, or —S(═O)2—O—.

29. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 28, wherein A5 represents a single bond.

30. The compound or a pharmaceutically acceptable salt thereof according to claim 29, wherein R2 represents an optionally substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms, an optionally substituted alicyclic hydrocarbon group having 3 to 8 carbon atoms, an optionally substituted aromatic hydrocarbon group having 6 to 14 carbon atoms, or an optionally substituted heterocyclic group.

31. The compound or a pharmaceutically acceptable salt thereof according to claim 29, wherein R2 represents an acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms, an alicyclic hydrocarbon group having 3 to 8 carbon atoms, an optionally substituted phenyl group, or an optionally substituted heterocyclic group having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom, or a sulfur atom, in the ring.

32. The compound or a pharmaceutically acceptable salt thereof according to claim 29, wherein R2 represents a cyclopropyl group, cyclobutyl group, cyclopropylmethyl group, methyl group, ethyl group, vinyl group, isopropyl group, or 2-methyl-1-propenyl group.

33. The compound or a pharmaceutically acceptable salt thereof according to claim 29, wherein R2 represents a thienyl group, a pyridyl group, a furyl group, a pyrrolyl group, a pyrazolyl group, or phenyl group; any of which may be further substituted by one or more of an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, an acyl group having 2 to 4 carbon atoms, a hydroxy group, a carboxyl group, an alkoxycarbonyl group having 2 to 7 carbon atoms, a fluorine atom, or a chlorine atom.

34. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 33, wherein A3 represents a single bond.

35. The compound or a pharmaceutically acceptable salt thereof according to claim 34, wherein R3 represents an optionally substituted aromatic hydrocarbon group having 6 to 14 carbon atoms.

36. The compound or a pharmaceutically acceptable salt thereof according to claim 34, wherein R3 represents a thienyl group, a pyridyl group, a furyl group, a pyrrolyl group, a pyrazolyl group, or phenyl group; any of which may be further substituted by one or more of an alkyl group having 1 to 4 carbon atoms.

37. The compound or a pharmaceutically acceptable salt thereof according to claim 34, wherein R3 represents a pyridyl group or a 1-oxypyridyl group, either of which may be further substituted by one alkyl group having 1 to 4 carbon atoms or one halogen atom; a pyrazolyl group; or N-methylpyrazolyl group.

38. The compound or a pharmaceutically acceptable salt thereof according to claim 29, wherein A6 represents a single bond.

39. The compound or a pharmaceutically acceptable salt thereof according to claim 32, wherein A6 represents a single bond, and R3 represents a pyridyl group or a 1-oxypyridyl group, either of which may be further substituted by one alkyl group having 1 to 4 carbon atoms or one halogen atom; a pyrazolyl group; or N-methylpyrazolyl group.

40. The compound or a pharmaceutically acceptable salt thereof according to claim 33, wherein A6 represents a single bond, and R3 represents a pyridyl group or a 1-oxypyridyl group, either of which may be further substituted by one alkyl group having 1 to 4 carbon atoms or one halogen atom; a pyrazolyl group; or N-methylpyrazolyl group.

41. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 23 to 28, wherein both of A5 and A6 represent a single bond.

42. The compound or a pharmaceutically acceptable salt thereof according to claim 41, wherein R2 represents an optionally substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms, an optionally substituted alicyclic hydrocarbon group having 3 to 8 carbon atoms, an optionally substituted aromatic hydrocarbon group having 6 to 14 carbon atoms, or an optionally substituted heterocyclic group, and R3 represents an optionally substituted aromatic hydrocarbon group having 6 to 14 carbon atoms or an optionally substituted heterocyclic group.

43. The compound or a pharmaceutically acceptable salt thereof according to claim 41, wherein R2 represents an optionally substituted acyclic aliphatic hydrocarbon group having 1 to 10 carbon atoms, an alicyclic hydrocarbon group having 3 to 8 carbon atoms, an optionally substituted phenyl group, or an optionally substituted heterocyclic group having 1 or 2 atoms selected from the group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom, in the ring, and R3 represents a thienyl group, a pyridyl group, a furyl group, a pyrrolyl group, a pyrazolyl group, or a phenyl group, any of which may be further substituted by one or more of a C1-C4 alkyl group.

44. The compound or a pharmaceutically acceptable salt thereof according to claim 41, wherein R2 represents a cyclopropyl group, methyl group, ethyl group, vinyl group, isopropyl group, isobutyl group, or 2-methyl-1-propenyl group, and R3 represents a pyridyl group or a 1-oxypyridyl group, either of which may be further substituted by one alkyl group having 1 to 4 carbon atoms or one halogen atom; pyrazolyl group; or N-methylpyrazolyl group.

45. The compound or a pharmaceutically acceptable salt thereof according to claim 41, wherein R2 represents a thienyl group, a pyridyl group, a furyl group, a pyrrolyl group, a pyrazolyl group, or a phenyl group, any of which may be further substituted by one or more of an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, or a chlorine atom, and R3 represents a pyridyl group or a 1-oxypyridyl group, either of which may be further substituted by one alkyl group having 1 to 4 carbon atoms or one halogen atom; pyrazolyl group; or N-methylpyrazolyl group.

46. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 45; and a pharmaceutically acceptable carrier.

47. A GSK-3 inhibitor comprising the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 45.

48. An agent for treating or preventing a GSK-3-mediated disease, comprising the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 45.

49. The agent for treating or preventing according to claim 48, wherein the GSK-3-mediated disease is selected from the group consisting of diabetes, diabetic complications, Alzheimer's disease, neurodegenerative disease, manic depressive psychosis, traumatic brain injury, alopecia, inflammatory disease, cancer, and immunodeficiency.

50. A compound represented by the formula (Ic):