UA101021C2 - Fused heterocyclic derivative and use thereof - Google Patents

Abstract

The present invention provides a compound having a superior Smo inhibitory activity and lower toxicity, which is sufficiently satisfactory as a pharmaceutical product The present invention provides a compound represented by the formula (I) wherein ring A is 5- to 7-membered ring optionally having substituent(s), where substituent(s) are optionally bonded to each other to form a ring; X is O, S or NR(Ris a hydrogen atom or a hydrocarbon group optionally having substituent(s)); Ris carbamoyl optionally having substituent(s); and Ris hydroxy optionally having substituent(s), or a salt thereof.

Description

Field of invention

The presented invention relates to a condensed heterocyclic derivative and its application.

More specifically, the present invention relates to a compound having strong inhibitory activity and is suitable for the prevention or treatment of cancer, and its use.

Prerequisites for creating an invention

The study of morphogenesis during the developmental stage was carried out on the basis of variant screening using Yugozorpya. The Neddepod gene (pi) was discovered as one of the genes that causes a morphological abnormality in the development of the Drosophila embryo due to its mutation. Product

The Neddepod gene (NI) is a secretory protein that is formed as an approximately 45 kDa precursor and then splits, as a result of autolysis, into a 20 kDa M-terminal flanking domain, which is the major active component, and a 25 kDa C-terminal flanking domain. The 20 KDa M-terminal side domain, which is the main active component, is modified with a fatty acid at the M-terminal end and cholesterol at its C-terminal end. The signal transduction system of the hedgehog (Neadepod) is formed by the protein group described below. The NI receptor is Raispey (Ris), which is a type twelfth transmembrane protein. Ris acts on Ztoyepei (Zto), which is a transmembrane protein of the seventh type, and inhibits (suppresses) the action of Zto in the absence of NI. When NI binds to the Risia receptor, the suppression of Zto is relieved and Zito is activated. The signal that occurs during activation

Therefore, it activates the transcription of factor C, which regulates the expression of a group of genes involved in morphogenesis (non-patent document 1).

A pathway corresponding to the JuOgozorpya Neddepod signal transduction system has also been confirmed in mammals. In humans, for example, three types of gene products are known, Zopis peadepod (PM),

Ipaiiap peddepod (Ipy) and Oezeag peddepod (OPp), corresponding to UOgozorpia NI, are subject to post-translational modification, as in Ogozorpia Ni (non-patent document 2). In human ZPP, the 19 kDa active component is cleaved from the 45 kDa precursor protein by autolysis, and a fatty acid and cholesterol are added to the M-terminal end and C-terminal end, respectively (non-patent document 3).

It is believed that such a modification must be decisive for maintaining 5PP activity and, for example, a 40-fold increase in activity was achieved by adding palmitic acid to recombinant human ZPP EzsPpegispia soybean, which did not have fatty acid modifications at the M-terminal end, and a 160-fold increase in activity was achieved by adding myristic acid (non-patent document 4). On the other hand, human Zto is known as the human gene corresponding to Ogo5orpya to, and two types RisNI1 and Risn2 are known as the human gene corresponding to Ogozorpiya Risr. In addition, it is believed that the transcription factor corresponding to YuOgozorpya SI should be in humans

CII, and known C types C1Ii1, Cii2 and CIIZ (non-patent document 5). BPALIAP/OPIA everyone contacts RISN! and activates 5to by inhibiting the connection between RiSp1 and Zto. ZPPLYYP/OpY also bind to Risyp2,

Kidneys, Ca51 and Cao/Vos, in addition to Risp1, regulate the activation of that. Signal transduction from Zto causes intranuclear localization (Ci(i1) and Sii2, and activates the transcription of Sii1 (non-patent document 6).

Nedydepod signaling in mammals is also involved in morphogenesis at developmental stages. In humans, for example, patients with arinencephaly, which is a congenital developmental abnormality, have had mutations in ZPP (non-patent document 7). In addition, the natural compound cyclopamine derived from chamomile, known as the compound that causes Susioria in sheep (non-patent document 8), has been confirmed to inhibit 5to by its mechanism of action (non-patent document 9). In addition, a 5Ppp knockout mouse was obtained and its phenotype was found to include Susioria, limb development pathology (Non-Patent Document 10), and neural plate development pathology (Non-Patent Document 11).

Neddepod signaling is essentially a developmental signal that is activated in tumor tissues and acts as a cancer cell growth and survival signal. It is believed that the Neddeipod signal in tumor tissues affects the growth and survival of cancer cells in an autocrine mode, or functions between cancer cells and cancer interstitial cells in a paracrine mode (non-patent document 12). In the autocrine mode, it works on the growth and maintenance of cancer cells through the activation of transcription under the influence of C1I-1, by controlling the abnormal cell cycle due to the increased expression of cyclin OY and the reduced expression of p21, stimulating the proliferation signal by activating the ESEK pathway, etc... On the other hand , in a paracrine mode, since the GPP expressed in cancer cells acts on 5to in cancer interstitial cells, growth factors such as insulin-like growth factor-1, fibroblast growth factor, platelet-derived growth factor and the like are transferred from cancer interstitial cells to cancer cells, and affect the growth and survival of cancer cells. It is believed that the stimulation of the MESE, ROSE pathway and the like under the influence of (1i-1) activates angiogenesis in the tumor (non-patent document 13). As for the mechanism of stimulation of the Nedeipod signal, it was reported about cancer in the process of development of which the Nedeipod signal is stimulated due to the mutation of Risp! , and cancer whose development is stimulated by overexpression of 5PY, which is one of the 3 ligands (non-patent document 14). Basal cell carcinoma and medulloblastoma are known as cancers whose development is stimulated by Neddeiod signaling due to mutation, and Risp1 mutations observed in these varieties cancer, activate the Neddeipod signal in a ligand-independent manner (non-patent document 15).

Pancreatic cancer (Non-Patent Document 16) and the like have been reported as cancers in which the Neddepod signal is stimulated by overexpression of ZPP. In a transgenic mouse in which 5pPp is forced to be expressed in the pancreas, Neddeipod signaling is believed to be involved not only in the growth and maintenance of cancer, but also in the oncogenic process, since a RapiMm-like lesion was detected in the pancreas at the initial stages of cancer development (non-patent document 17). In addition, it is believed that Neddepod signaling affects the growth and survival of cancer stem cells and plays a key role in metastasis or postoperative recurrence of tumor growth and the like (non-patent document 18).

The following compounds are known as inhibitors of the Neddeiod signal. Cyclopamine, which is a natural inhibitory compound, has been reported to have a suppressive effect on tumor growth in glioma (non-patent document 19) and the like. SOC-61414 (non-patent document 20) and BAMT-1, 2, 3, 4 (non-patent document 21) were reported as synthetic low molecular weight compounds that inhibit Zto.

It has been reported with respect to the Neddeipod signaling inhibitory antibody that administration of the anti-5pi antibody to a toli' (thymusless) mouse transplanted with HT-29 colorectal cancer cells caused regression of the cancer (Patent Document 1).

As a compound similar to the compound described herein, Patent Document 2 describes the following compounds having antibacterial activity. s, go SON, SON, pkne same 5 5 these TO , DU in KU ; rt on

I be i zak i tod g E i

E E E and more E s k , shk soch, t SOny, du Z and 5 so, roya razrya o | this and and ; I b Me y Ka i ky AF I: nia Kk E is vit is SOchnsche A Soie, som, o is E a r s

S syu t Ky g t D Z

As a compound having antibacterial activity, patent document C describes the following compounds. but 0

With M

ОН 3-4 o,

M - A OSOMN(SN) CM ! M 5; - patent document 1: UMO2004/020599 patent document 2: UR-А-3-223289 patent document 3: М/О93/1 3664 non-patent document 1: Sigt. Orip. Sepoys Oeyem., volume 12, p. 503-511 (2002) Non-Patent Document 2: Proceedings, Vol. 103, p. 371-374 (2000) non-patent document 3: .). Vioi Spet., volume 273, p. 14037-14045 (1998) Non-Patent Document 4: Viospetizigo, Vol. 40, p. 4359-4371 (2001) Non-Patent Document 5: Maiige Keu. Sapseg, volume 2, p. 361-372 (2002) non-patent document 6: Sitgt. Orip. Sow! Vioi., volume 19, p. 159-165 (2007) Non-Patent Paper 7: Mai. Sepei., volume 14, p. 357-360 (1996)

non-patent document 8: At. in. May Kev., volume 24, p. 1164-1175 (1963) Non-Patent Document 9: OemeIortepi, Vol. 125, p. 3553-3562 (1998) Non-Patent Document 10: Maishge, Vol. 383, p. 407-413 (1996) Non-Patent Document 11: Journal, Vol. 111, p. 63-75 (2002) Non-Patent Paper 12: Mai. Kew. Ogyd Oizsom., volume 5, p. 1026-1033 (2006) non-patent document 13: Siip Sapseg Kev., volume 12, p. 5924-5928 (2006) Non-Patent Document 14: Maishige Chem. Sapseg, volume 3, p. 903-911 (2003) non-patent document 15: At. .). Honey. Sep., volume 123A, p. 5-28 (2003) Non-Patent Document 16: Maishge, Vol. 425, p. 846-851 (2003) Non-Patent Document 17: Maishge, Vol. 425, p. 851-856 (2003) Non-Patent Document 18: Tgepaz Seyi Vio!., Vol. 17, p. 438-227 (2007) Non-Patent Document 19: OemeIortepi, Vol. 128, p. 5201-5212 (2001) non-patent document 20: Rhos. Mai). Asai. All together. 0O.5.A., volume 100, p. 4616-4621 (2003) non-patent document 21: Rhos. Mai! Asai. 5 O.5.A., volume 99, p. 14071-14076 (2002)

Disclosure of the invention

Problems solved by the invention

The task of this invention is to obtain a compound that has an extraordinary ZTO inhibitory activity, low toxicity and sufficiently meets the requirements as a pharmaceutical product.

The authors of this invention conducted intensive research in an effort to solve the above-mentioned problems and found that the compound represented by the following formula and its salt have strong 5to inhibitory activity, which was the completion of this invention.

Accordingly, the objects of the presented invention are: 1) A compound represented by the following formula

IN

H

2-8

A (0) 0 in which A is a 5- to 7-membered ring, optionally having a substituent(s), wherein the substituents are optionally bonded to each other to form a ring;

X means O, 5 or MK (B! is a hydrogen atom or a hydrocarbon group, which does not necessarily have a substituent(s));

IN? means carbamoyl optionally having substituent(s); and

BZ means hydroxy, optionally having a substituent(s), except for the following compounds;

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Pn I would 5 LNie and .:

In no: z, di and I A, 5 days Te I vn o tsk -ooochnisniueya my Du a un and shk. oh yes and

Yes --y E E E s, Fin, sen, x I x TO o An r koe a. Ko Ku g. their o

Because yes; took uv in o and shk and preak same mk me

E in va E is I oh, "Z s syny ssashe

On the 5th of Thursday on Zv KA znii r ER i i o i i: iz sho x tn Gde iye shen E R: shle ov to VK me, Dom ne ii M iche no: Od kur osn u Zh pk in si o chia (hereinafter abbreviated as compound (I)) or its salts.

And(2| Compound, defined above in 1), which is represented by formula 2

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VAD? and 3 x | (7) pe and (c) vi in which

MIN? and 83 are as defined in the aforementioned clause (11,

DAM and rAlg are the same or different and each is a hydrogen atom or a substituent, or VLA and Ale are optionally bonded to each other to form a 5- to 7-membered ring that optionally has a substituent(s) , and

IN? means a hydrogen atom or a hydrocarbon group optionally having a substituent(s) (hereinafter sometimes referred to as compound (173).

ИЗ)Й The compound defined above in 2), which is represented by the formula where ; schi vl A. U Z rn A

Her (7

What is your opinion?

MIN? and 83 are as defined in the aforementioned clause (11,

VA Its 272 are the same or different and each is a hydrogen atom or a substituent, and

B" means a hydrogen atom or an optionally substituted hydrocarbon group (hereinafter sometimes referred to as compound (1).

I4Y The compound defined above in (III, in which X is O, 5 or M(C-C alkyl),

B2 means carbamoyl, optionally having a substituent(s),

BZ means hydroxy, optionally having C -C alkyl, optionally having a substituent(s),

B" means a hydrogen atom or C: is an alkyl group,

Ve means a hydrogen atom or C: there is an alkyl group, and

B" means a hydrogen atom or a C-C alkyl, which optionally has a substituent(s).

IB) The compound defined above in 1), which is represented by the formula c

X by y y

In with mo (about in" in which

MIN? and 83 are as defined in the above clause (11, ring B is a b--lene ring optionally having substituent(s); and

IN? means a hydrogen atom or a hydrocarbon group optionally having a substituent(s) (hereinafter sometimes referred to as compound (1).

A compound as defined in (5) above, wherein ring B is a b-membered ring optionally having substituent(s),

X means 0, 5 or M(C.-C alkyl),

IN? means carbamoyl, optionally having substituent(s),

BZ means hydroxy, optionally having C-C alkyl, optionally having substituent(s) and

B" means a hydrogen atom or an optionally substituted C3-C6 alkyl.

IL M-P1-(2-Hydroxyethyl)piperidin-4-yl|-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5- dihydro-1H-pyrrolyl3 ,2-c|quinoline-2-carboxamide or its salt.

IVI M-P-"Hydroxyacetyl)piperidin-4-yl|-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5- dihydro-1H-pyrroloyi3,2 -c|quinoline-2-carboxamide or its salt.

III) 3-Ethoxy-6-ethyl-N-(1-(hydroxyacetyl)piperidin-4-yl|-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro -1H-pyrroloyi3,2-c|Ipyridine-2-carboxamide or its salt.

HO) M-P-"Hydroxyacetyl)piperidin-4-yl|-1,6-dimethyl-4-oxo-5-(2-oxo-2-phenylethyl)-3-(2,2,2-trifluoroethoxy)- 4,5-dihydro-1H-pyrrolo|3,2-s|Ipyridine-2-carboxamide or its salt.

HI b-EEthyl-M-HP1-("hydroxyacetyl)piperidin-4-yl|-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-3-(2,2,2- trifluoroethoxy )-4,5-dihydro-1H-pyrrolo|3,2-s|Ipyridine-2-carboxamide or its salt. (12) Prodrugs of the compound defined in (11) above. (13) Pharmaceutical agent containing the compound defined in (11) above or its prodrugs.

І14|І The pharmaceutical agent defined in item (131) above, which is a 5-Ito inhibitor.

І15)І The pharmaceutical agent defined in clause (13) above, which is an agent for the prevention or treatment of cancer.

I16Ї The method of inhibiting 5to in a mammal, which includes administering to the mammal an effective amount of the compound defined above in item (11), or its prodrugs.

I17| A method of preventing or treating cancer in a mammal, which comprises administering to the mammal an effective amount of the compound defined in (11) above, or a prodrug thereof.

І18І Use of the compound defined above in clause (1|І) or its prodrugs for obtaining 5th inhibitor.

I19| Use of a compound as defined in clause |11| above, or its prodrugs, to produce an agent for the prevention or treatment of cancer.

In this description, compound (I) includes compound (I), compound (I) and compound (17). (Effectiveness of the invention)

Since the compound of the present invention has a strong To inhibitory effect, it can be a clinically useful agent for the prevention or treatment of cancer, an inhibitor of cancer development, and an agent that inhibits cancer metastasis. (Detailed description of the invention)

The present invention is explained in detail below.

In compound (), X is O, 5 or MA (B' is a hydrogen atom or a hydrocarbon group, optionally having a substituent(s)).

Examples of an "optionally substituted hydrocarbon group(s) for B" include optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl (s), optionally substituted cycloalkyl, optionally substituted aryl, and the like.

Examples of "alkyl" for "optionally substituted alkyl" mentioned above include C 1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl , hexyl) and the like.

Examples of the substituent for the above-mentioned "optionally substituted alkyl(s)" may include the following "group A substituents" and the like, and in the attached position(s) may be present from 1 to 5 (preferably from 1 to 3) substituents: (Substituents of group A) (1) halogen atom (for example, fluorine atom, chlorine atom, bromine atom, iodine atom), (2) cyano, (3) C-C alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl), optionally having 1 to 3 substituents selected from (1U C-o aryl (eg, phenyl, naphthyl), (2 ) amino, (33 Gray alkoxycarbonylamino (e.g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino), (4) hydroxy, (5 C:.v alkoxy (e.g., methoxy, ethoxy, propoxy)) and (6) heterocyclic groups (e.g., pyrrolidinyl, benzodioxolyl ), (4) C 1-6 alkenyl (e.g. vinyl, allyl), (5) C 1-6 alkynyl (e.g. ethynyl, propargyl), (6) C 3-6 cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl) , optionally having one hydroxy group, (7) C1-0 aryl (e.g., phenyl, naphthyl), optionally having from 1 to 3 substituents selected from (a) a halogen atom (e.g., a fluorine atom, a chlorine atom ), (B) hydroxy, (c) cyano, (a) C1-6 alkylsulfonyl (e.g., methylsulfonyl), and (e) C1-6 alkoxy (e.g., methoxy, ethoxy, propoxy), which optionally having 1-3 halogen atoms (e.g., a fluorine atom), (8) C alkylcarbonyl (e.g., acetyl, ethylcarbonyl, propylcarbonyl, butylcarbonyl), optionally having 1 to 3 substituents selected from (1 hydroxy, (23 (e.g., methoxy, ethoxy), (3) amino, (4) C. alkylamino (e.g., methylamino, ethylamino, propylamino, isopropylamino), (5 C. alkylsulfonyl (e.g., methylsulfonyl), and (6 ) C-6 alkylcarbonyloxy (e.g., methylcarbonyloxy), (9) C-6 arylcarbonyl (e.g., benzoyl, naphthoyl), optionally having 1 to 3 substituents selected from (a) a halogen atom (e.g., a chlorine atom) , and (5) Civ Alkoxy (e.g. methoxy), (10) carbamoyl, (11) C.e. alkylcarbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl), which optionally has one hydroxy group, (12) di-Ci-e alkylcarbamoyl (e.g., dimethylcarbamoyl, diethylcarbamoyl), (13) ) Arylcarbamoyl group (e.g., phenylcarbamoyl, naphthylcarbamoyl), (14) 5- - 7-membered cyclic carbamoyl (e.g., 1-pyrrolidinylcarbonyl, 1-piperidylcarbonyl, 1-piperazinylcarbonyl, 4-morpholinylcarbonyl, 4-thiomorpholinylcarbonyl, 1-homopiperazinylcarbonyl), (15) carboxyl, (16) Lower alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl), (17) Lower aryloxycarbonyl (e.g., phenoxycarbonyl), (18) amino, optionally having 1 or 2 substituents selected from (a ) C1-6 alkoxycarbonyl (eg, tert-butoxycarbonyl), and (p) C1-6 alkylcarbonyl (eg, methylcarbonyl), optionally having one hydroxy or C1-6 alkylcarbonyloxy (eg, methylcarbonyloxy), (19) Ci. alkylamino (eg methylamino, ethylamino, propylamino, isopropylamino, butylamino),

(20) di-C:-e alkylamino (e.g., dimethylamino, diethylamino, dipropylamino), optionally having one hydroxy, (21) C.e. alkylcarbonylamino (e.g., acetylamino, ethylcarbonylamino), optionally having from! to C substituents selected from (a) C1-6 alkylcarbonyloxy (e.g. methylcarbonyloxy), (5) C1-6 alkoxy (e.g. methoxy) and (c) hydroxy, (22) di-(C1-6 alkylcarbonyl)lamino (e.g., di-(acetyl)amino, di-(ethylcarbonyl)amino, di-(propylcarbonyl)amino), (23) Si alkoxycarbonylamino (e.g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, tert-butoxycarbonylamino), (24) M-Si -6 alkyl-M-(C1-is alkylcarbonyl)amino (for example, M-acetyl-M-methylamino, M-acetyl-M-ethylamino), (25) ureido, (26) C:-is alkylureido (for example, methylureido , ethyl ureido), (27) hydroxy, (28) C 1-6 alkoxy (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy), which optionally has 1-3 St- o aryl (e.g., phenyl), (29) C-o aryloxy (e.g., phenoxy, naphthoxy), (30) a heterocyclic group (e.g., a 5- or b--membered aromatic heterocyclic group such as 1-pyrrolyl, 2- pyridyl, Z-pyridyl, 4-pyridyl, 1-pyrazolyl, 1-imidazolyl, 2-imidazolyl, 2-p irazinyl, 2-furyl, 2-thiazolyl, 4-pyrimidinyl and the like; 3- - 8-ene non-aromatic heterocyclic group such as 3-azetidinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-piperidyl, 2-piperidyl, 3-piperidyl, 4-piperidyl, 1-piperazinyl, 1 -morpholinyl, morpholino, 2-tetrahydrofuryl, tetrahydrothiopyran-4-yl, tetrahydropyran-4-yl, 3-azepanyl, 4-azepanyl and the like; a group obtained by condensation of a non-aromatic heterocyclic group such as 1,3-benzodioxol-b-yl and the like and a benzene ring) optionally having 1 to 3 (preferably 1 or 2) substituents selected from (1U C .i.6 alkyl (e.g., methyl, ethyl, propyl), optionally having 1 to 3 substituents selected from (a) a halogen atom (e.g., a fluorine atom), and (B) hydroxy, (2) hydroxy . (e.g., tert-butoxycarbonyl), and (9) C 1 -C 6 alkylcarbonyl (e.g., acetyl, propionyl), optionally having 1 to 3 substituents selected from (a) hydroxy, (5) C 1 -C 6 alkoxy (e.g., methoxy, ethoxy, propoxy), (c) amino, (8) Civ alkylamino (e.g. methylamino, ethylamino, propylamino, isopropylamino), (e) di-C:1-ev alkylamino (e.g. dimethylamino) and ()) Civ alkylcarbonyloxy ( for example, methylcarbonyloxy), (31) oxo, (32) thiox o, (33) Lower alkylsulfonyl (e.g., methylsulfonyl), (34) Heterocyclylcarbonyl (e.g., pyrrolidinylcarbonyl, tetrahydrofurylcarbonyl).

Examples of "alkenyl" for "optionally substituted alkenyl" mentioned above include

Examples include alkenyl (eg, vinyl, allyl) and the like.

Examples of the substituent for the above-mentioned "optionally substituted alkenyl(s)" include the above-mentioned group A substituents and the like, and in the attached position(s) may be present from 1 to 5 (preferably from 1 to 3 ) substitutes.

Examples of "alkynyl" for "optionally substituted alkynyl" mentioned above include

Cg-v alkynyl (for example, ethynyl, propargyl) and the like.

Examples of the substituent for the above-mentioned "optionally substituted alkynyl(s)" may include the above-mentioned group A substituents and the like, and in the attached position(s) may be present from 1 to 5 (preferably from 1 to 3) substitutes.

Examples of "cycloalkyl" for the above-mentioned "cycloalkyl optionally having substituent(s)" include C3-E cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl) and the like.

Examples of the substituent for the above-mentioned "cycloalkyl optionally having substituent(s)" may include (1) the above-mentioned group A substituents, (2) C 1-6 alkyl optionally having 1 to 3 substituents selected from the above-mentioned group substituents And similar, and in the given position(s) may be present from 1 to 5 (mostly from 1 to 3) substituents.

In addition, "cycloalkyl, which does not necessarily have a substituent(s) can be a group obtained by the condensation of C3-6 cycloalkyl and a benzene ring (for example, 1,2,3,4-tetrahydronaphthalen-1-yl).

Examples of "aryl" for the above-mentioned "aryl optionally having substituent(s)" include C-10 aryl (eg, phenyl, naphthyl) and the like.

Examples of the substituent for the above-mentioned "aryl optionally having substituent(s)" may include (1) the above-mentioned Group A substituents (excluding oxo and thioxo), (2) C 1 -C alkyl optionally having 1 to C substituents selected from the above group A substituents and the like, and in the attached position(s) 1 to 5 (preferably 1 to 3) substituents may be present.

X is preferably O, 5 or ME" (B' is alkyl, optionally having a substituent(s)), and particularly preferably, 0, 5 or M(C:-C alkyl) (in particular, M(methyl)) .

B2 means carbamoyl, optionally having a substituent(s). Examples of "carbamoyl optionally having substituent(s)" for K2 include (1) carbamoyl optionally having 1 or 2 substituent(s) selected from the group consisting of "hydrocarbon group optionally having substituent(s) " and "heterocyclic group optionally having substituent(s)", (2) cyclic carbamoyl optionally having substituent(s) and the like.

Examples of the above-mentioned "hydrocarbon group optionally having a substituent(s)" include examples similar to the above-mentioned "hydrocarbon group optionally having a substituent(s) for K.

Examples of the "heterocyclic group" for the above-mentioned "heterocyclic group optionally having a substituent(s)" and the "heterocyclic group" given as an example of a substituent that may have the aforementioned "alkyl optionally having a substituent(s) and the like include an aromatic heterocyclic group and a saturated or unsaturated non-aromatic heterocyclic group (aliphatic heterocyclic group), each of which contains as a component atom of the ring system (ring atom) from 1 to 3 species (predominantly 1 or 2 species) of at least one (predominantly 1 -4, more preferably 1 or 2) from heteroatoms selected from an oxygen atom, a sulfur atom (the sulfur atom can be oxidized) and a nitrogen atom, and a group having a bond at a carbon atom, and the like.

Examples of an "aromatic heterocyclic group" include (1) a 5- or b-membered monocyclic aromatic heterocyclic group such as furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1 ,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanil, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1 ,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like, and (2) an 8- to 12-membered condensed polycyclic aromatic heterocyclic group such as benzofuranyl, isobenzofuranyl, benzo|B|hienyl, indolyl , isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-bezoisoxazolyl, benzothiazolyl, benzopyranyl, 1,2-benzoisothiazolyl, -1H- benzotriazolyl, quinolyl, isoquinolyl, cinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteryl carbazolyl, c-carbolinyl, p-carbolinyl, y-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiinyl, thianthrenyl, phe nantridinyl, phenatrolinyl, indolizinyl, pyrrolo|1,2-b|Ipyridazinyl, pyrazolo!|1,5-a|pyridyl, imidazo|1,2-a|pyridyl, imidazo|1,5-a|pyridyl, imidazo|1 ,2-B|Ipyridazinyl, imidazo(1,2-a|Ipyrimidinyl, 1,2,4-triazolo|4,3-a|Ipyridyl, 1,2,4-triazolo|4,3-

Bipyridazinil and the like, and the like.

Examples of "non-aromatic heterocyclic group" include (1) a 3- - β-h-lene (preferably 5- or b-h-lene) saturated or unsaturated (preferably saturated) non-aromatic heterocyclic group (aliphatic heterocyclic group) such as oxyranil, azepanil , azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thioranyl, piperidyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, piperazinyl, and the like, (2) a non-aromatic heterocyclic group in which a double bond in the aforementioned monocyclic aromatic heterocyclic group or condensed polycyclic aromatic heterocyclic group is partially or fully saturated, such as 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl and the like, and (3) a group in which the non-aromatic heterocyclic group, such as benzodioxolyl and the like , and the benzene ring is condensed and the like.

Examples of a "substituent" for the above-mentioned tetracyclic group optionally having substituent(s)" include (1) the above-mentioned group A substituents, (2) substituents similar to those mentioned for the above-mentioned "hydrocarbon group optionally having substituent(s) (preferably C1-C alkyl optionally having 1 to 3 substituents selected from the above group A substituents) and the like, and the substituents in suitable amounts may be present at suitable position(s) .

As cyclic carbamoyl in "cyclic carbamoyl optionally having substituent(s)", 5- to 7-membered cyclic carbamoyl is used, and examples thereof include pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, piperazin-1-ylcarbonyl , morpholine-4-ylcarbonyl, thiomorpholine-4-ylcarbonyl, homopiperazin-1-ylcarbonyl and the like.

Examples of "substituent" in "cyclic carbamoyl optionally having substituent(s) include the above-mentioned group A substituents and the like, and at suitable position(s) may be present 1-

With substitutes.

In addition, the "cyclic carbamoyl" substituent(s) optionally having the substituent(s) may be linked to each other to form a 5- to 7-membered ring. In other words, the 5- to 7-membered ring and the cyclic carbamoyl may form a fused ring system A fused ring system includes a spiro-fused ring system.

Examples of a 5- to 7-membered ring include (1) a 5- to 7-membered homocyclic ring (e.g., cyclohexane, cyclohexene, cyclohexanediene, cycloheptane, benzene), and (2) a 5- to 7-membered heterocycle (e.g. , piperidine, piperazine, morpholine, thiomorpholine, pyridine, pyrazine, pyrimidine, pyridazine, triazine, pyran, dihydropyran, tetrahydropyran, 1,3-dioxole). Among them, cyclohexane ring, benzene ring and 1,3-dioxole ring are preferred.

As 22 preference is given to (A) carbamoyl, which optionally has 1 or 2 substituents selected from the group consisting of (1) Sub-alkyl, optionally having 1 or 2 (preferably 1) substituents selected from (1) halogen atom, (2) cyano, (3) amino, (4) C..v alkylamino, (5 di-C:-is alkylamino, which optionally has one hydroxy, (6) Si-is alkoxycarbonylamino, (7 ) hydroxy, (8 di-C:1-e alkylcarbamoyl, (9 5- - 7-membered cyclic carbamoyl, (10) heterocyclic group, which optionally has from 1 to 3 (preferably 1) substituents selected from (a ) hydroxy, (5) C:-e alkyl, optionally having one hydroxy, (c) oxo, (a) C:-e alkoxycarbonyl, and (e) C:-e alkylcarbonyl, optionally having from 1 to C (preferably 1) substituents selected from C1-6 alkylcarbonyloxy and hydroxy, (11 C.6 alkoxycarbonyl, (12 C3.e cycloalkyl, which optionally has one hydroxy), (13) C:-in alkoxy, ( 14) Cg-v alkynyl, (15) Cg-o aryl, which optionally has 1-3 (preferably 1 or 2) C.i.e. alkoxy, (16) carbamoyl, and (17 C. alkylcarbo nylamino, optionally having 1 to 3 (preferably 1) substituents selected from (a) C 1 -C 6 alkylcarbonyloxy, (5) C 1 -C 6 alkoxy, and (c) hydroxy, (2) C 3 -C 6 cycloalkyl or 1, 2,3,4-tetrahydronaphthalenyl, optionally having 1 or 2 substituents selected from (1U, amino, optionally having one substituent selected from (a) C:1-6 alkoxycarbonyl, and (5) C - is alkylcarbonyl, which optionally has from 1 to 3 (preferably 1) substituents selected from hydroxy and C. - is alkylcarbonyloxy, (2) hydroxy, (3) carboxy,

(4) C1-6 hydroxycarbonyl, (5) C1-6 alkylcarbamoyl, optionally having one hydroxy, (6) C1-6 alkyl, optionally having one hydroxy, and (7) C1-6 alkylcarbonylamino (eg, tert-butoxycarbonylamino), (3) C1-6 aryl, and (4) a heterocyclic group, which optionally has from 1 to 4 (preferably 1) substituents selected from (1C1-6alkyl, which optionally necessarily has from 1 to 5 substituents selected from (a) C1-10 aryl, (B) hydroxy, and (c) a halogen atom, (2) C1-6 alkylcarbonyl, optionally having from 1 to C (preferably 1 ) substituents selected from (a) C 1-6 alkylcarbonyloxy, (b) hydroxy, (c) C 1-6 alkoxy, (a) C 1-6 alkylsulfonyl, and (e) amino, (3) C 1-6 alkoxycarbonyl, and (43 5- or b-membered aromatic heterocyclic group, which optionally has from 1 to 3 (preferably 1) substituents selected from (a) C:-e alkyl, which optionally has 1-3 halogen atoms, (p) cyano, (c) carbamoyl, (8) C:-e alkoxy, and (e) C:-c alkylcarbamoyl, (5) oxo, (6) C:-6 alkylcarbamoyl, (7) C:-c alkylsulfonyl, (8) C- io aryl, optionally having 1 to 3 (preferably 1) substituents selected from (a) hydroxy, (p) cyano, and (c) C 10 alkylsulfonyl, (9) heterocyclylcarbonyl, and (103 C-10 aryloxycarbonyl (e.g. , phenoxycarbonyl), (8) 5- - 7--ene cyclic carbamoyl, which optionally has from 1 to 3 (preferably 1) substituents selected from the group consisting of (1) C 1-6 alkyl, optionally having from 1 to C (preferably 1) substituents selected from (a) a heterocyclic group, (p) amino, (c) C 1-6 alkoxy, and (a) C 1-6 aryl, (2) amino, optionally having one C 1-6 alkylcarbonyl, (3) M-C 1-6 alkyl-M-(C 1-6 alkylcarbonyl)amino, (4) heterocyclic group, (5) C 1-6 alkylcarbonyl, optionally having one substituent selected from (a) hydroxy, (5) C:-in alkoxy, (c) amino, (8) Si. alkylamino, (ie) di-C:-ie alkylamino, and (I) C-C alkylcarbonyloxy, (6) C-C aryl, and (7) oxo, or (C) 5- to 7-membered cyclic carbamoyl, condensed with a 5- to 7-membered ring.

WZ means hydroxy, optionally having a substituent(s). As a "substituent" for "hydroxy, optionally having substituent(s)" for KZ, the aforementioned "hydrocarbon group optionally having substituent(s) for EC", the aforementioned "teterocyclic group, optionally" necessarily has a substitute(s)" and the like.

As Preferred are hydroxy optionally having alkyl optionally having a substituent(s), more preferred are hydroxy optionally having (1) C 1-6 alkyl optionally having one C 1-6 alkoxy, (2) C1-C alkyl optionally having from 1 to 5 (preferably 1-3) halogen atoms, (3) C1-C alkyl optionally having one C1-10 aryl, or

(4) C 1-6 alkyl, optionally having one heterocyclic group, and even more preferably hydroxy, substituted with (1) C 1-6 alkyl, optionally having one C 1-6 alkoxy, (2) C 1-6 alkyl , which optionally has from 1 to 5 (mostly 1-3) halogen atoms, (3) C 1-6 alkyl, optionally having one C 1-10 aryl, or (4) C 1-6 alkyl, optionally having one heterocyclic group.

Ring A is a 5- to 7-membered ring, optionally having substituent(s). As "5- - 7-membered ring" for "5-- 7-membered ring optionally having substituent(s)" for ring A may be specified (1) 5- - 7-membered a hollow homocyclic ring (e.g., cyclohexane, cyclohexene, cyclohexanediene, cycloheptane, benzene), and (2) a 5- to 7-membered heterocycle (e.g., piperidine, piperazine, morpholine, thiomorpholine, pyridine, pyrazine, pyrimidine, pyridazine, triazine, pyran , dihydropyran, tetrahydropyran, 1,3-dioxol).

Examples of a "substituent" that may have a "5- to 7-membered ring" in the definition of a "5- to 7-membered ring optionally having substituent(s)" for ring A include (1) the aforementioned Group A substituents , (2) substituents similar to those of the aforementioned "hydrocarbon group optionally having substituent(s)" (preferably C1-E alkyl optionally having 1 to 3 substituents selected from the above group A substituents ) and the like, and substituents in suitable amounts may be present at suitable position(s).

In addition, as "substituent" which may have "5- to 7-membered ring" for "5- to 7-membered ring optionally having substituent(s)" for ring A, two substituents are optional necessarily connected to each other to form a ring. As a ring formed by such "substituents" connected to each other, we can mention (1) a 5- to 7-membered homocyclic ring (for example, cyclohexane, cyclohexene, cyclohexanediene, cycloheptane, benzene), and (2) 5 - - 7-membered heterocycle (eg, piperidine, piperazine, morpholine, thiomorpholine, pyridine, pyrazine, pyrimidine, pyridazine, triazine, pyran, dihydropyran, tetrahydropyran, 1,3-dioxole).

The ring formed by the substituents of ring A which are bonded to each other may have a substituent(s), and examples of the substituents include (1) the above-mentioned group A substituents, (2) substituents similar to those of the above-mentioned "hydrocarbon group that are "necessarily has a substituent(s)" (preferably C 1 -C alkyl, optionally having 1 to 3 substituents selected from the above group A substituents) and the like, and the substituents in a suitable amount may be present in the suitable ) position(s).

Compound (I), in particular, has a structure represented by the following formula

? 2 2 2 2

K I K and in V

X- Yes! X- X- X X X - ! Z ke more Zh z hv AH x i oh r ; WITH

BULL ASINYU AYU l re

U Z o ko xx M-- 0 0 0 0 0 But 0 ? t 2? ?

K K K K K

XX dz xx z AH dz x- z KU ov re K zho K A K Sha - « ee K

НМ 0 5 A

A, A, Y A, A po i) Ko i o Mo

H from 2 2 2

В В В в" sk Kn sk ЧИ НО I х- х-й рон no и no no НВ в

С 13 / А, Й A in GA au, I dya o p in shshch 07 mb 000 ho

N

2 2 ? 7

K KE K y - --4

ХУ dz ХУ з xx Z x- Z

F-x K - K She K and 5-I

A uye g / k NK le

See in Cl a p i p o NN v

M 0 -mKHM

Н Н in which the rings from Ai to Ago optionally additionally have a substituent(s), the substituents are optionally bonded to each other to form a ring, -СН»-СНе- part that is a component of the ring in the case of the Ag ring , rings A?7, rings Av, rings A», rings Ago, rings A, rings Ag, rings Ana, rings Ag5, rings

Av, rings A!1?7, rings Av, rings A" and rings Ago is not necessarily transformed into -"СН-СН-, -МН-СНе- the part that is a component of the ring in the case of the ring Ах, the ring А5, the ring Av, rings A, rings Aiiz, rings

A 5, rings Av and rings Ago are optionally converted to -M-CH-, and the symbols are as defined above.

As a substituent that may have rings A: to Ago, substituents similar to the "substituents" that "5- to 7-membered ring" may have in the definition of "5- to 7-membered ring having optionally has "substituent(s)" for the A ring.

As a compound (I), the compound represented by the formula is preferable?

What the hell

AND

M 0 4

K in which each symbol is as defined above.

Among the above-mentioned compounds, compound (17) represented by the formula is preferred

MORE

"-vA2 ho 3 x | (t) te-AMOTM o)

These are in which X, B? and EZ are as defined above, KLA! and CAlg are the same or different, and each is a hydrogen atom or a substituent, or BA and Ale are optionally bonded to each other to form a 5- to 7-membered ring, optionally having a substituent(s) , and K" is a hydrogen atom or a hydrocarbon group, which optionally has a substituent(s).

Compound (I") is described in detail below.

X, 82 and Z are as defined above.

B is a hydrogen atom or a hydrocarbon group, optionally having a substituent(s). As "hydrocarbon group optionally having substituent(s)" for EC" may be specified groups similar to those mentioned above as "hydrocarbon group optionally having substituent(s) for KK.

As B" preferred is a hydrogen atom or alkyl optionally having a substituent(s). In particular, preference is given to (1) a hydrogen atom, (2) C 1-6 alkyl optionally having one substituent selected from (1U C3.v cycloalkyl, (23 C1-0 aryl, which optionally has (i) 1 or 2 C-6 alkoxy, which optionally has from 1 to 3 halogen atoms or (ii) from 1 to 3 atoms halogen, (3) C-6 alkylcarbonyl, (4) C-6 arylcarbonyl, which does not necessarily have one halogen atom or C-6 alkoxy, (5) C-6 alkoxycarbonyl, (6) C-6 arylcarbamoyl, ( 7) a heterocyclic group, which does not necessarily have 1 or 2 C..6 alkyl, which does not necessarily have from 1 to 3 halogen atoms, (8) C1-0 aryloxy, (9) carboxy, (10 cyano and (11 ) C:-1 alkoxy, optionally having one C1-10 aryl, (3) C:1-1 alkyl, optionally having from 1 to 3 halogen atoms and the like.(1) VAM her B? Al and A are the same or different and each is a hydrogen atom or a substituent. by ring A.

How VA! hydrogen atom or C..v alkyl group are preferred.

As 22 preferred is a hydrogen atom or a C-C alkyl group.

Alternatively, (2) VAM and KA? are linked to each other to form a 5- to 7-membered ring, which optionally has a substituent(s). As "5- to 7-membered ring optionally having substituent(s)" may be specified substituents similar to those mentioned above as substituents of "5- to 7-membered ring optionally has substituent(s), for ring A. In suitable positions, a 5- to 7-membered ring does not necessarily have a suitable number of substituents.

In the first embodiment, among the above-mentioned compounds (I"), preference is given to compound (I) represented by the formula in

In ;

Why not.

K in which X, KE? and EZ are as defined above, ring B is a b-membered ring optionally having a substituent(s), and 2 is a hydrogen atom or a hydrocarbon group optionally having a substituent(s) in which

VAAT and VAL? are linked to each other to form a b-membered ring, which optionally has a substituent(s).

Compound (I) is described in detail below.

X, 82, VZ and E are as defined above.

In formula (I), preferred examples of K2 include (A) carbamoyl, optionally having 1 or 2 substituents selected from (1) C 1 alkyl (eg, methyl, ethyl, propyl, isopropyl, n-butyl, 2-methylpropyl, 2,2- dimethylpropyl, 1-methylbutyl, 1-ethylpropyl), optionally having 1 or 2 substituents selected from (1) a halogen atom (eg, a fluorine atom), (2) cyano, (3) amino, ( 4) C.v alkylamino (e.g., isopropylamino), (5) di-C:1-6e alkylamino (e.g., dimethylamino, diethylamino, di-i-propylamino), which optionally has one hydroxy, (6) C- is alkoxycarbonylamino (e.g., tert-butoxycarbonylamino), (7) hydroxy, (8 di-C:1-e alkylcarbamoyl (e.g., diethylcarbamoyl), (9 5- to 7-membered cyclic carbamoyl (e.g., 1-pyrrolidinylcarbonyl), ( 10) heterocyclic group (for example, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-pyrazolyl, 1-imidazolyl, 1-piperidyl, 2-piperidyl, 3-piperidyl, 4-piperidyl, 1-piperazinyl, 1-morpholinyl , morpholino, 2-pyridyl, 3-pyridyl, 4-pyr idyl, 2-pyrazinyl, 2-furyl, 2-tetrahydrofuryl, 1,3-benzodioxol-5-yl) optionally having one (a) hydroxy, (5) C:-C alkyl (e.g. methyl, ethyl ), optionally having one hydroxy, (c) oxo, (a) C 1-6 alkoxycarbonyl (e.g., tert-butoxycarbonyl), or (e) C 1-6 alkylcarbonyl (e.g., methylcarbonyl), optionally having one substituent selected with

Alkylcarbonyloxy (e.g., methylcarbonyloxy) and hydroxy, (11) C.6 alkoxycarbonyl (e.g., ethoxycarbonyl), (123 C) cycloalkyl (e.g., cyclopropyl, cyclohexyl) optionally having one hydroxy, (13 C:.e.alkoxy (e.g., methoxy, i-propoxy), (14) C 1 -e alkynyl (e.g., ethynyl), (15) C 1 -o aryl (e.g., phenyl), optionally having 1 or 2 C 1 6 alkoxy (e.g., methoxy ), (16) carbamoyl, and (173 Civ alkylcarbonylamino (e.g., methylcarbonylamino) optionally having one substituent selected from (a) C:1-e alkylcarbonyloxy (e.g., methylcarbonyloxy), (5) C:-e alkoxy (e.g. methoxy) and (c) hydroxy, (2) C3-e cycloalkyl (e.g. cyclopropyl, cyclohexyl) or 1,2,3,4-tetrahydronaphthalenyl (e.g. 1,2,3,4-tetrahydronaphthalene-1 -yl) optionally having 1 or 2 substituents selected from (1U, amino optionally having one substituent selected from (a) C 1-6 alkoxycarbonyl (eg, tert-butoxycarbonyl), and (p) C-e alkylcarbonyl (e.g ad, methylcarbonyl), optionally having one hydroxy or C1-6 alkylcarbonyloxy (e.g., methylcarbonyloxy), (2) hydroxy, (3) carboxy, (4) C1-6 alkoxycarbonyl (e.g., methoxycarbonyl), (5) Si . alkylcarbamoyl (e.g., ethylcarbamoyl) optionally having one hydroxy, (6) C 1-6 alkyl (e.g., methyl) optionally having one hydroxy, and (7) C 1-6 hydroxycarbonylamino (e.g., tert -butoxycarbonylamino), (3) S-o aryl (e.g., phenyl), and (4) heterocyclic group (e.g., 3-azetidinyl, 3-pyrrolidinyl, 4-piperidyl, 2-tetrahydrofuryl, 3-azepanyl, 4-azepanyl, tetrahydrothiopyran-4-yl, tetrahydropyran-4-yl), which optionally has from 1 to 4 substituents selected from (1U C.i.6 alkyl (for example, methyl, ethyl, n-propyl)), which optionally has 1 to 5 substituents selected from

(a) Se-o aryl (e.g., phenyl), (B) hydroxy, and (c) a halogen atom, (2) Se-o alkylcarbonyl (e.g., methylcarbonyl, ethylcarbonyl, i-propylcarbonyl, i-butylcarbonyl), which necessarily has one substituent selected from (a) C1-6 alkylcarbonyloxy (e.g. methylcarbonyloxy), (b) hydroxy, (c) C1-6 alkoxy (e.g. methoxy), (a) C1-6 alkylsulfonyl (e.g. , methylsulfonyl), and (e) amino, (3) C-e alkoxycarbonyl (e.g., tert-butoxycarbonyl), (43 5- or b-membered aromatic heterocyclic group (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl , 2-thiazolyl, 4-pyrimidinyl), optionally having one substituent selected from (a) C1-6 alkyl (e.g., methyl), optionally having 1-3 halogen atoms (e.g., a fluorine atom), ( p) cyano, (c) carbamoyl, (8) C:-6 alkoxy (e.g., methoxy) and (e) C:1-6 alkylcarbamoyl (e.g., methylcarbamoyl), (5) oxo, (6) C:-6 alkylcarbamoyl (e.g., ethylcarbamoyl), (7) C:i.-v alkylsulfonyl (e.g., methylsulfonyl), (8) Sv -o aryl (e.g., phenyl) optionally having one substituent selected from (a) hydroxy, (p) cyano, and (c) C 1 alkylsulfonyl (e.g., methylsulfonyl), (9) heterocyclylcarbonyl (e.g., 2-pyrrolidinylcarbonyl, 2-tetrahydrofurylcarbonyl), and (10) S-o aryloxycarbonyl (e.g., phenoxycarbonyl), (B) 5- to 7-membered cyclic carbamoyl (e.g., 1-pyrrolidinylcarbonyl, 1-piperidylcarbonyl, 1-piperazinylcarbonyl, 1-homopiperazinylcarbonyl, morpholinocarbonyl , thiomorpholinocarbonyl) optionally having one substituent selected from (1) C alkyl (e.g., methyl, ethyl) optionally having one substituent selected from (a) a heterocyclic group (e.g., 1-pyrrolidinyl, benzodioxol- 5-yl), (B) amino, (c) C 1-6 alkoxy (e.g. methoxy) and (8) C 1-6 aryl (e.g. phenyl), (2) amino optionally having one C 1-6 alkylcarbonyl (e.g., acetyl), (3) M-Ci-C alkyl-M-(C1-e alkylcarbonyl)amino (e.g., M-acetyl-M-ethylamino), (4) heterocyclic group (e.g., 1-pyrrolidinyl y, 2-pyridyl), (5) Alkylcarbonyl group (e.g., acetyl, propionyl), optionally having one substituent selected from (a) hydroxy, (5) Alkoxy group (e.g., methoxy, ethoxy), (c ) amino, (8) C:-e alkylamino (e.g., isopropylamino), (e) di-C:1-e alkylamino (e.g., dimethylamino) and ()) C:-e alkylcarbonyloxy (e.g., methylcarbonyloxy), (6) Sv- io aryl (e.g., phenyl), and (7) oxo, and (C) 5- to 7-membered cyclic carbamoyl fused with a 5- to 7-membered ring (e.g., cyclohexane ring, benzene ring, 1,3-dioxole ring) (for example, 1-piperidylcarbonyl).

In formula (I), preferred examples of KZ include hydroxy, optionally having (1) C 1-6 alkyl (e.g., methyl, ethyl, n-butyl), optionally having one (a) C 1-6 alkoxy (e.g. , ethoxy), (5) C 1-10 aryl (e.g., phenyl), or (c) a heterocyclic group (e.g., 4-pyridyl, morpholino, 2-tetrahydrofuryl), or (2) C 1-10 alkyl (e.g., methyl, ethyl) , which optionally has 1-3 halogen atoms (for example, a fluorine atom)

And preferably, hydroxy substituted with (1) C 1-6 alkyl (e.g. methyl, ethyl, n-butyl) optionally having one (a) C 1-6 alkoxy (e.g. ethoxy),

(5) C1-10 aryl (e.g., phenyl), or (c) a heterocyclic group (e.g., 4-pyridyl, morpholino, 2-tetrahydrofuryl), or (2) C1-10 alkyl (e.g., methyl, ethyl), which is necessarily has 1-3 halogen atoms (for example, a fluorine atom)|.

In formula (I), preferred examples of KK" include (1) a hydrogen atom, (2) C 1-6 alkyl (e.g., methyl, ethyl, n-propyl, n-butyl, n-pentyl, i-pentyl, 2-ethylbutyl), optionally having one substituent selected from (17) C3-C6 cycloalkyl (e.g., cyclopropyl, cyclohexyl), (23 C1-C6 aryl (e.g., phenyl), optionally having (u) one C1-C6-6 alkoxy ( e.g., methoxy) optionally having 1 to 3 halogen atoms (e.g., a fluorine atom) or (ii) 1 to 3 halogen atoms (e.g., a fluorine atom, a chlorine atom), (3) C 1 alkylcarbonyl (e.g., methylcarbonyl , tert-butylcarbonyl), (4) Ct-o arylcarbonyl (e.g., benzoyl), (5) C-6 alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl), (6) Ct-o arylcarbamoyl (e.g., phenylcarbamoyl) , (7) a heterocyclic group (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl, 1-pyrrolyl, 2-imidazolyl, 2-furyl, 2-tetrahydrofuryl) optionally having 1 or 2 alkyl groups (e.g. , methyl), which does not necessarily have 1-3 gal atoms (e.g., a fluorine atom), (8) C 1-6 aryloxy (e.g., phenoxy), (9) carboxy, (10) cyano, and (11) C 1-6 alkoxy (e.g., methoxy), optionally having one C 1-10 aryl (eg, phenyl) and (3) C 1-6 alkyl (eg, ethyl), optionally having 1-3 halogen atoms (eg, a fluorine atom).

Ring B is a b-membered ring, optionally having substituent(s). As a b-membered ring" for "6-membered ring optionally having substituent(s)" can be specified (1) a homocyclic ring (e.g., cyclohexane, cyclohexene, cyclohexanediene, benzene), and (2) a heterocycle (e.g. , piperidine, piperazine, morpholine, thiomorpholine, pyridine, pyrazine, pyrimidine, pyridazine, triazine, pyran, dihydropyran, tetrahydropyran).

Examples of the substituent that ring B may have include (1) the aforementioned Group A substituents, (2) C 1 -C alkyl optionally having 1 to 3 substituents selected from the aforementioned Group A substituents and the like, and the substituents in a suitable amount may be present in the appropriate position(s).

As ring B, optionally substituted cyclohexene ring, optionally substituted benzene ring, or optionally substituted pyridine ring are preferred, and cyclohexene is more preferred ring, a benzene ring optionally having one halogen atom (eg, a fluorine atom), or a pyridine ring. In particular, the benzene ring and the pyridine ring are preferred.

Among the compounds (I), preference is given to the compound in which the ring B is a β-ene ring, which optionally has a substituent(s),

X means 0, 5 or M(C.-C alkyl),

B2 means carbamoyl, optionally having a substituent(s),

BZ means hydroxy, optionally having C-C alkyl, optionally having substituent(s), and

B" means a hydrogen atom or an optionally substituted C3-C6 alkyl.

Specific examples of preferred compounds (I) include the following.

IS performance (1-1)

Compound (G), in which

X means O, 5 or M(C-C alkyl) (in particular, M(methyl));

IN? means (A) carbamoyl, optionally having 1 or 2 substituents selected from (1) C alkyl (eg, methyl, ethyl, propyl, isopropyl, 2,2-dimethylpropyl, 1-methylbutyl), optionally having one substituent selected from (1) halogen atom (eg, fluorine atom), (2) cyano, (3) amino, (4) C.i.v alkylamino (eg, isopropylamino), (53 di-Ci-e alkylamino (e.g., dimethylamino, diethylamino), optionally having one hydroxy, (6) C1-e alkoxycarbonylamino (e.g., tert-butoxycarbonylamino), (7) hydroxy,

(8 di-C:1-e alkylcarbamoyl (for example, diethylcarbamoyl), (9) 5- - 7-membered cyclic carbamoyl (for example, 1-pyrrolidinylcarbonyl), (10) heterocyclic group (for example, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-pyrazolyl, 1-imidazolyl, 1-piperidyl, 2-piperidyl, 3-piperidyl, 4-piperidyl, 1-piperazinyl, 1-morpholinyl, 2-pyridyl, 3-pyridyl), which optionally has one (a) hydroxy, or (5) C1-6 alkyl (e.g., methyl, ethyl), optionally having one hydroxy, and (11) C1-6 hydroxycarbonyl (e.g., ethoxycarbonyl), (2) C3-e cycloalkyl ( e.g., cyclohexyl) optionally having 1 or 2 substituents selected from (1) amino and (2) hydroxy, (3) C-6 aryl (e.g., phenyl) and (4) heterocyclic group (e.g., 3-pyrrolidinyl , 4-piperidyl) optionally having one C-- in alkyl (e.g. methyl) optionally having 1 or 2 substituents selected from (a) Ce-o aryl (e.g. phenyl), and ( B) hydroxy, or (B) 5- - 7-membered cyclic carbamoyl (for example, 1-pyrrolidine lcarbonyl, 1-piperidylcarbonyl, 1-homopiperazinylcarbonyl) optionally having one substituent selected from (1) C alkyl (eg, methyl, ethyl) optionally having one substituent selected from (a) a heterocyclic group ( e.g., 1-pyrrolidinyl, benzodioxol-5-yl) and (p) amino, (2) amino, (3) M-C 6 -alkyl-M-(C 1 -alkylcarbonyl)amino (e.g., M-acetyl-M -ethylamino), (4) a heterocyclic group (e.g., 1-pyrrolidinyl), and (5) a Civ alkylcarbonyl (e.g., acetyl, propionyl) optionally having one substituent selected from (a) hydroxy, (5) Civ alkoxy (eg methoxy), (c) amino and (8) C alkylamino (eg isopropylamino);

BZ means hydroxy, which optionally has C3-C6 alkyl (eg, methyl, ethyl), which optionally has one C3-C6 alkoxy (eg, ethoxy);

B" means (1) a hydrogen atom, or (2) C 1-6 alkyl (e.g., methyl, ethyl) optionally having one substituent selected from (17) C 3-6 cycloalkyl (e.g., cyclopropyl), (23 C- o aryl (e.g., phenyl) optionally having one C 1-6 methoxy (e.g., methoxy), (3) C 1-6 alkylcarbonyl (e.g., tert-butylcarbonyl), (4) C 1-6 arylcarbonyl (e.g., benzoyl), (5) C-6 alkoxycarbonyl (e.g., ethoxycarbonyl), (6) N-o arylcarbamoyl (e.g., phenylcarbamoyl), (7) heterocyclic group (e.g., 2-pyridyl), (8) N-o aryloxy ( eg, phenoxy) and (9) carboxy; and ring B is a benzene ring.

IS (1I-2))

Compound (I), where

X means O, 5 or M(C-C alkyl) (in particular, M(methyl));

Bg means (A) carbamoyl, optionally having 1 or 2 substituents selected from (1) C 1 -C alkyl (eg, methyl, ethyl, propyl, isopropyl, 2-methylpropyl, 2,2-dimethylpropyl, 1-methylbutyl), which optionally has 1 or 2 substituents selected from (1) halogen atom (eg, fluorine atom), (2) cyano, (3) amino, (4) C.i.v alkylamino (eg, isopropylamino), ( 53 di-Ci-e alkylamino (e.g., dimethylamino, diethylamino) optionally having one hydroxy, (6) Ci-e alkoxycarbonylamino (e.g., tert-butoxycarbonylamino), (7) hydroxy, (8 di-C:1 - is alkylcarbamoyl (for example, diethylcarbamoyl), (9 5- - 7-membered cyclic carbamoyl (for example, 1-pyrrolidinylcarbonyl),

(10) heterocyclic group (for example, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-pyrazolyl, 1-imidazolyl, 1-piperidyl, 2-piperidyl, 3-piperidyl, 4-piperidyl, 1-piperazinyl, 1- morpholinyl, 2-pyridyl, 3-pyridyl), optionally having one (a) hydroxy or (B) C:-1 alkyl (e.g., methyl, ethyl), optionally having one hydroxy, (11) Si .6 alkoxycarbonyl (e.g. ethoxycarbonyl), and (12) C 3 -e cycloalkyl (e.g. cyclohexyl), (2) C 3 -e cycloalkyl (e.g. cyclohexyl) optionally having 1 or 2 substituents selected from (1 amino and (2) hydroxy, (3) C-o aryl (e.g., phenyl) and (4) heterocyclic group (e.g., 3-pyrrolidinyl, 4-piperidyl) optionally having one substituent selected from (1 Ci .6 alkyl (e.g. methyl) optionally having 1 or 2 substituents selected from (a) C1-0 aryl (e.g. phenyl) and (B) hydroxy, (23 Civ alkylcarbonyl (e.g. methylcarbonyl)) that optionally has one substituent selected from (a) C:-C alkylcarbonyloxy (e.g. iklad, methylcarbonyloxy) and (B) hydroxy, (3) C 1-6 alkoxycarbonyl (e.g., tert-butoxycarbonyl) and (4) a 5- or b-membered aromatic heterocyclic group (e.g., 4-pyridyl) or (B) 5- - 7-membered cyclic carbamoyl (for example, 1-pyrrolidinylcarbonyl, 1-piperidylcarbonyl, 1-homopiperazinylcarbonyl) optionally having one substituent selected from (1) Civ alkyl (for example, methyl, ethyl), which necessarily has one substituent selected from (a) a heterocyclic group (e.g., 1-pyrrolidinyl, benzodioxol-5-yl) and (p) amino, (2) amino, (3) M-C1-C alkyl-M-(C1 -is an alkylcarbonyl)amino (e.g., M-acetyl-M-ethylamino), (4) a heterocyclic group (e.g., 1-pyrrolidinyl), and (5) an alkylcarbonyl group (e.g., acetyl, propionyl), optionally having one substituent , selected from (a) hydroxy, (5) Civ alkoxy (eg, methoxy), (c) amino, and (8) Civ alkylamino (eg, isopropylamino);

BZ means hydroxy, which optionally has (1) C 1-6 alkyl (e.g., methyl, ethyl), optionally having one C 1-6 alkoxy (e.g., ethoxy), or (2) C 1-6 alkyl (e.g., methyl , ethyl), which optionally has 1-3 halogen atoms (for example, a fluorine atom)

And preferably, hydroxyl substituted with (1) C 1-6 alkyl (e.g., methyl, ethyl) optionally having one C 1-6 alkoxy (e.g., ethoxy), or (2) C 1-6 alkyl (e.g., methyl, ethyl) optionally having must have 1-3 halogen atoms (for example, a fluorine atom)|;

B" means (1) a hydrogen atom or (2) C 1-6 alkyl (e.g., methyl, ethyl) optionally having one substituent selected from (17) C 3-6 cycloalkyl (e.g., cyclopropyl), (23 C 1-6 aryl (e.g., phenyl) optionally having one C-6 alkoxy (e.g., methoxy), (3) C-6 alkylcarbonyl (e.g., tert-butylcarbonyl), (4) C1-0 arylcarbonyl (e.g., benzoyl ), (5) C-6 alkoxycarbonyl (e.g., ethoxycarbonyl), (6) N-o arylcarbamoyl (e.g., phenylcarbamoyl), (7) heterocyclic group (e.g., 2-pyridyl), (8) N-o aryloxy (e.g. , phenoxy) and (9) carboxy; and ring B is a cyclohexene ring or a benzene ring (especially a benzene ring).

Compound (I-3)

Compound (G), in which

X means O, 5 or M(C-C alkyl) (in particular, M(methyl));

IN? means

(A) carbamoyl, optionally having 1 or 2 substituents selected from (1) C 1 alkyl (eg, methyl, ethyl, propyl, isopropyl, n-butyl, 2-methylpropyl, 2,2-dimethylpropyl, 1-methylbutyl , 1-ethylpropyl), which optionally has 1 or 2 substituents selected from (1) a halogen atom (for example, a fluorine atom), (2) cyano, (3) amino, (4) C.i.v alkylamino ( e.g., isopropylamino), (5) di-C:1-6e alkylamino (e.g., dimethylamino, diethylamino, di-i-propylamino), optionally having one hydroxy, (6) C1-e alkoxycarbonylamino (e.g., tert- butoxycarbonylamino), (7) hydroxy, (8 di-C:1-e alkylcarbamoyl (e.g., diethylcarbamoyl), (9 5- - 7-membered cyclic carbamoyl (e.g., 1-pyrrolidinylcarbonyl), (10) heterocyclic group (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-pyrazolyl, 1-imidazolyl, 1-piperidyl, 2-piperidyl, 3-piperidyl, 4-piperidyl, 1-piperazinyl, 1-morpholinyl, morpholino, 2-pyridyl, Z-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-furyl, 2-tetrahydro ryl, 1,3-benzodioxol-5-yl), optionally having one (a) hydroxy, (5) C:1-C alkyl (eg, methyl, ethyl), optionally having one hydroxy, ( c) oxo, (8) C 1-6 alkoxycarbonyl (e.g. tert-butoxycarbonyl) or (e) C 1-6 alkylcarbonyl (e.g. methylcarbonyl), optionally having one substituent selected

C Siv of alkylcarbonyloxy (e.g., methylcarbonyloxy) and hydroxy, (11) C.6 alkoxycarbonyl (e.g., ethoxycarbonyl), (123 Csv of cycloalkyl (e.g., cyclopropyl, cyclohexyl), which optionally has one hydroxy, (13 C:.e methoxy (e.g., methoxy, i-propoxy), (14) C 1 -e alkynyl (e.g., ethynyl), (15) C 1 -e aryl (e.g., phenyl), optionally having 1 or 2 C 1 6 alkoxy (e.g., methoxy), (16) carbamoyl and (173Ci alkylcarbonylamino (e.g., methylcarbonylamino) optionally having one substituent selected from (a) C:i-e alkylcarbonyloxy (e.g., methylcarbonyloxy), (5) C:-e alkoxy (e.g. methoxy) and (c) hydroxy, (2) C3-e cycloalkyl (e.g. cyclopropyl, cyclohexyl) or 1,2,3,4-tetrahydronaphthalenyl (e.g. 1,2,3,4-tetrahydronaphthalene-1 -yl) optionally having 1 or 2 substituents selected from (1U, amino optionally having one substituent selected from (a) C 1-6 alkoxycarbonyl (eg, tert-butoxycarbonyl) and (B) C alkylcarbonyl (eg e, methylcarbonyl) which optionally has one hydroxy or C1-6 alkylcarbonyloxy (eg, methylcarbonyloxy), (2) hydroxy, (3) carboxy, (4) C1-6 alkoxycarbonyl (eg, methoxycarbonyl), (5) Si . alkylcarbamoyl (e.g., ethylcarbamoyl) optionally having one hydroxy, (6) C 1-6 alkyl (e.g., methyl) optionally having one hydroxy, and (7) C 1-6 hydroxycarbonylamino (e.g., tert -butoxycarbonylamino), (3) S-o aryl (e.g., phenyl) and (4) heterocyclic group (e.g., 3-azetidinyl, 3-pyrrolidinyl, 4-piperidyl, 2-tetrahydrofuryl, 3-azepanyl, 4-azepanyl, tetrahydrothiopyran -4-yl, tetrahydropyran-4-yl), optionally having from 1 to 4 substituents selected from (1U C-6 alkyl (eg, methyl, ethyl, n-propyl), optionally having from 1 up to 5 substituents selected from (a) Ce-o aryl (e.g., phenyl), (p) hydroxy, and (c) halogen, (2) Ce-o alkylcarbonyl (e.g., methylcarbonyl, ethylcarbonyl, i-propylcarbonyl, i-butylcarbonyl ), optionally having one substituent selected from (a) C1-6 alkylcarbonyloxy (e.g. methylcarbonyloxy), (b) hydroxy, (c) C1-6 alkoxy (e.g. methoxy),

(a) C:i-e alkylsulfonyl (e.g., methylsulfonyl) and (e) amino, (3) C:i-e alkoxycarbonyl (e.g., tert-butoxycarbonyl), (43 5- or b-membered aromatic heterocyclic group (e.g., 2 -pyridyl, 3-pyridyl, 4-pyridyl, 2-thiazolyl, 4-pyrimidinyl) optionally having one substituent selected from (a) C 1-6 alkyl (e.g. methyl) optionally having 1- 3 halogen atoms (e.g., a fluorine atom), (p) cyano, (c) carbamoyl, (8) C:-e alkoxy (e.g., methoxy), and (e) C:i-e alkylcarbamoyl (e.g., methylcarbamoyl), ( 5) oxo, (6) C1-6 alkylcarbamoyl (for example, ethylcarbamoyl), (7) C1-6 alkylsulfonyl (for example, methylsulfonyl), (8) C1-6 aryl (for example, phenyl), which is optional has one substituent selected from (a) hydroxy, (p) cyano, and (c) C 1 -alkylsulfonyl (e.g., methylsulfonyl), (9) heterocyclylcarbonyl (e.g., 2-pyrrolidinylcarbonyl, 2-tetrahydrofurylcarbonyl), and (10) C 1 -o aryloxycarbonyl (for example, phenoxycarbonyl), (B) 5- - 7-membered cyclic c arbamoyl (e.g., 1-pyrrolidinylcarbonyl, 1-piperidylcarbonyl, 1-piperazinylcarbonyl, 1-homopiperazinylcarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl), optionally having one group selected from (1) alkyl (e.g., methyl, ethyl), optionally necessarily has one substituent selected from (a) a heterocyclic group (e.g., 1-pyrrolidinyl, benzodioxol-5-yl), (p) amino, (c) C 1 -C 6 alkoxy (e.g., methoxy), and (8) C 1 -C 0 aryl (e.g., phenyl), (2) amino optionally having one C1-6 alkylcarbonyl (e.g., acetyl), (3) M-C1-6 alkyl-M-(C1-6 alkylcarbonyl)amino (e.g., M-acetyl-M-ethylamino), (4) a heterocyclic group (eg, 1-pyrrolidinyl, 2-pyridyl), (5) an alkylcarbonyl group (eg, acetyl, propionyl), optionally having one substituent selected from ( a) hydroxy, (5) C 1 -C 6 alkoxy (e.g., methoxy, ethoxy), (c) amino, (8) C 6 alkylamino (e.g., isopropylamino), (e) di-C:1-C alkylamino (e.g., dimethylamino), and ()) Alkylcarbonyloxy seeds (for example, methyl carbo nilox), (6) S-io aryl (e.g., phenyl) and (7) oxo, or (C) 5- to 7-membered cyclic carbamoyl (e.g., 1-piperidylcarbonyl) fused to a 5- to 7-membered ring (for example, cyclohexane ring, benzene ring, 1,3-dioxole ring);

BZ means hydroxy, optionally having (1) C 1-6 alkyl (e.g., methyl, ethyl, n-butyl), optionally having one (a) C 1-6 alkoxy (e.g., ethoxy), (5) C 1-10 aryl (e.g., phenyl), or (c) a heterocyclic group (e.g., 4-pyridyl, morpholino, 2-tetrahydrofuryl), or (2) C 1-10 alkyl (e.g., methyl, ethyl), optionally having 1- 3 halogen atoms (for example, a fluorine atom)

And preferably, hydroxy substituted with (1) C 1-6 alkyl (e.g., methyl, ethyl, n-butyl) optionally having one (a) C 1-6 alkoxy (e.g., ethoxy), (5) C 1-10 aryl (e.g., phenyl) or (c) a heterocyclic group (e.g., 4-pyridyl, morpholino, 2-tetrahydrofuryl), or (2) C 1 alkyl (e.g., methyl, ethyl) optionally having 1-3 halogen atoms ( for example, a fluorine atom)|;

B" means (1) a hydrogen atom, (2) C 1-6 alkyl (eg, methyl, ethyl, n-propyl, n-butyl, n-pentyl, i-pentyl, 2-ethylbutyl), optionally having one substituent , selected from (17) C3-6 cycloalkyl (for example, cyclopropyl, cyclohexyl),

(23 Sv-lo aryl (e.g., phenyl) optionally having (i) one Ci- alkoxy (e.g., methoxy), optionally having 1-3 halogen atoms (e.g., a fluorine atom) or (ii) from 1 to 3 halogen atoms (for example, a fluorine atom, a chlorine atom), (3) C alkylcarbonyl (for example, methylcarbonyl, tert-butylcarbonyl), (4) C-o arylcarbonyl (for example, benzoyl), (5) C-6 alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl), (6) N-O arylcarbamoyl (e.g., phenylcarbamoyl), (7) heterocyclic group (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl, 1-pyrrolyl, 2-imidazolyl, 2-furyl, 2-tetrahydrofuryl) optionally having 1 or 2 C:-6 alkyl (e.g. methyl) optionally having 1-3 halogen atoms (e.g. fluorine atom), ( 8) C 1-6 aryloxy (e.g. phenoxy), (9) carboxy, (10 cyano and (11) C 1-6 alkoxy (e.g. methoxy), optionally having one C 1-10 aryl (e.g. phenyl) , or (3) C 1 alkyl (e.g., ethyl) optionally having 1-3 gal atoms oxygen (for example, a fluorine atom); and ring B is a cyclohexene ring, a benzene ring optionally having one halogen atom (for example, a fluorine atom), or a pyridine ring (in particular, a benzene ring and a pyridine ring).

IS performance (1-4)

M-H1-(2-hydroxyethyl)piperidin-4-yl|-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolyl3, 2-si|quinoline-2-carboxamide;

M-P1-"hydroxyacetyl)piperidin-4-yl|-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolyl3,2- si|quinoline-2-carboxamide; or their salt.

In another embodiment, among the compounds (I") defined above, preference is given to compound (1), represented by the formula ве 4 с вы р КМ х--д3

Its (7) is a formula in which X, 2, BZ and EB" are as defined above, and B" and 272 are the same or different and each is a hydrogen atom or a substituent.

Compound (I") is described in detail below.

X, B, BZ, and B are as defined above.

In formula (I), preferred examples of P are (A) carbamoyl, optionally having 1 or 2 substituents selected from (1) C alkyl (eg, methyl, ethyl, propyl, isopropyl, 2-methylpropyl, 2,2-dimethylpropyl, 1-methylbutyl), optionally having 1 or 2 substituents selected from (1) a halogen atom (eg, a fluorine atom), (2) cyano, (3) amino, (4) C. i.v alkylamino (e.g., isopropylamino), (53 di-Ci-e alkylamino (e.g., dimethylamino, diethylamino), which optionally has one hydroxy, (6) Ci-e alkoxycarbonylamino (e.g., tert-butoxycarbonylamino), ( 7) hydroxy, (8 di-C:1-e alkylcarbamoyl (for example, diethylcarbamoyl), (9 5- - 7-membered cyclic carbamoyl (for example, 1-pyrrolidinylcarbonyl), (10) heterocyclic group (for example, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-pyrazolyl, 1-imidazolyl, 1-piperidyl, 2-piperidyl, 3-piperidyl, 4-piperidyl, 1-piperazinyl, 1-morpholinyl, 2-pyridyl, 3-pyridyl, 2- tetrahydrofuryl) optionally having one (a) hydroxy, or

(5) C1-6 alkyl (e.g., methyl, ethyl), optionally having one hydroxy, (11 C1-6 alkoxycarbonyl (e.g., ethoxycarbonyl) and (12) C3-e cycloalkyl (e.g., cyclohexyl), ( 2) C3-e cycloalkyl (e.g., cyclohexyl) optionally having 1 or 2 substituents selected from (1) amino and (2) hydroxy, (3) C1-0 aryl (e.g., phenyl), and (4) a heterocyclic group (e.g., 3-pyrrolidinyl, 4-piperidyl, 5-oxido-tetrahydrothiopyran-4-yl), optionally having one substituent selected from (1C-16 alkyl (e.g., methyl), optionally having 1 or 2 substituents selected from (a) C1-0 aryl (e.g., phenyl) and (B) hydroxy, (23C alkylcarbonyl (e.g., methylcarbonyl), optionally having one substituent selected from (a) C:-e alkylcarbonyloxy (e.g., methylcarbonyloxy) and (B) hydroxy, (3) C 1-6 alkoxycarbonyl (e.g., tert-butoxycarbonyl) and (4) 5- or b-membered aromatic heterocyclic group (e.g., 4-pyridyl), or (B) 5- - 7-membered cyclic carbamoyl (e.g. 1-pyrrolidinylcarbonyl, 1-piperidylcarbonyl, 1-homopiperazinylcarbonyl) optionally having one substituent selected from (1) C alkyl (e.g., methyl, ethyl) optionally having one substituent selected from (a) a heterocyclic group (e.g., 1-pyrrolidinyl, benzodioxol-5-yl) and (p) amino, (2) amino, (3) M-Ci-C alkyl-M-(C1-e alkylcarbonyl)amino (e.g., M-acetyl- M-ethylamino), (4) a heterocyclic group (e.g., 1-pyrrolidinyl), and (5) Civ alkylcarbonyl (e.g., acetyl, propionyl), optionally having one substituent selected from (a) hydroxy, (5) Civ alkoxy (e.g. methoxy), (c) amino and (8) C alkylamino (e.g. isopropylamino).

In formula (17), EZ preferably means hydroxy, which optionally has (1) C1-6 alkyl (e.g., methyl, ethyl, n-propyl, i-propyl), which optionally has one C1-6 alkoxy (e.g. , ethoxy), or (2) C-C alkyl (e.g., methyl, ethyl, n-propyl, i-propyl) optionally having 1-3 halogen atoms (e.g., a fluorine atom)

And preferably, hydroxyl substituted with (1) C 1-6 alkyl (e.g., methyl, ethyl) optionally having one C 1-6 alkoxy (e.g., ethoxy), or (2) C 1-6 alkyl (e.g., methyl, ethyl) optionally having must have 1-3 halogen atoms (for example, a fluorine atom)|.

In formula (17), KE" preferably means (1) a hydrogen atom or (2) C 1-6 alkyl (e.g., methyl, ethyl) optionally having one substituent selected from (17) C 3-C cycloalkyl (e.g., cyclopropyl ), (23 C 1-6 aryl (e.g., phenyl) optionally having (i) 1 or 2 C:1-6 alkoxy (e.g., methoxy), or (ii) 1 to 3 halogen atoms (e.g., chlorine atom), (3) C-6 alkylcarbonyl (e.g., tert-butylcarbonyl), (43 C) arylcarbonyl (e.g., benzoyl), which optionally has one halogen atom (e.g., chlorine atom) or C..v. alkoxy ( e.g., methoxy), (5) C-6 alkoxycarbonyl (e.g., ethoxycarbonyl), (6) C-6 arylcarbamoyl (e.g., phenylcarbamoyl), (7) heterocyclic group (e.g., 2-pyridyl), (8) C-o aryloxy (eg, phenoxy) and (9) carboxy; i

BA" means a hydrogen atom or an alkyl group (eg, methyl, ethyl, n-propyl).

VA Its Ve are the same or different and each is a hydrogen atom or a substituent. Substituents similar to those of the above-mentioned ring A may be specified as a substituent.

A hydrogen atom or a C.-v alkyl group is preferable as E"".

As 22, a hydrogen atom or a C.-v alkyl group is preferred.

Among the compounds (I"), preference is given to the compound in which

X means 0, 5 or M(C.-C alkyl),

IN? means carbamoyl, optionally having substituent(s),

BZ means hydroxy, which optionally has C-C alkyl, which optionally has a substituent(s),

B" means a hydrogen atom or C. alkyl group (for example, methyl, ethyl, n-propyl),

Ve means a hydrogen atom or an alkyl group (for example, methyl) and

B" means a hydrogen atom or C. alkyl, which optionally has a substituent(s).

Specific examples of preferred compounds (I) include the following compounds.

IS performance (17-1)

Compound (I1"), in which

X means O, 5 or M(C-C alkyl) (in particular, M(methyl));

Bg means (A) carbamoyl, optionally having 1 or 2 substituents selected from (1) C 1 -C alkyl (eg, methyl, ethyl, propyl, isopropyl, 2-methylpropyl, 2,2-dimethylpropyl, 1-methylbutyl), which optionally has 1 or 2 substituents selected from (1) halogen atom (eg, fluorine atom), (2) cyano, (3) amino, (4) C.i.v alkylamino (eg, isopropylamino), ( 53 di-Ci-e alkylamino (e.g., dimethylamino, diethylamino) optionally having one hydroxy, (6) Ci-e alkoxycarbonylamino (e.g., tert-butoxycarbonylamino), (7) hydroxy, (8 di-C:1 - is alkylcarbamoyl (for example, diethylcarbamoyl), (9 5- - 7-membered cyclic carbamoyl (for example, 1-pyrrolidinylcarbonyl), (10) heterocyclic group (for example, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-pyrazolyl , 1-imidazolyl, 1-piperidyl, 2-piperidyl, 3-piperidyl, 4-piperidyl, 1-piperazinyl, 1-morpholinyl, 2-pyridyl, 3-pyridyl), optionally having one (a) hydroxy, or (5) C:-in alkyl (for example, methyl, ethyl), which is not required necessarily has one hydroxy, (11 C.6 alkoxycarbonyl (eg, ethoxycarbonyl) and (12) C3-e cycloalkyl (eg, cyclohexyl), (2) C3-e cycloalkyl (eg, cyclohexyl), which optionally has 1 or 2 substituents selected from (1 amino and (2) hydroxy, (3) C-o aryl (eg, phenyl) and (4) a heterocyclic group (eg, 3-pyrrolidinyl, 4-piperidyl), optionally having one substituent selected from (1 C1-6 alkyl (e.g. methyl) optionally having 1 or 2 substituents selected from (a) C1-6 aryl (e.g. phenyl) and (B) hydroxy, (23 C alkylcarbonyl (e.g. methylcarbonyl) optionally having one substituent selected from (a) C 1-6 alkylcarbonyloxy (e.g. methylcarbonyloxy) and (B) hydroxy, (3) C 1-6 alkoxycarbonyl (e.g. tert-butoxycarbonyl) and (4 5- or b-membered aromatic heterocyclic group (e.g., 4-pyridyl), or (B) 5- to 7-membered cyclic carbamoyl (e.g., 1-pyrrolidinylcarbonyl, 1-piperidylcarbonyl, 1-homopiperazinylcarbonyl), which 'I zkovo has one group selected from (1) C alkyl (e.g., methyl, ethyl) optionally having one substituent selected from (a) a heterocyclic group (e.g., 1-pyrrolidinyl, benzodioxol-5-yl) and ( p) amino, (2) amino, (3) M-C-C alkyl-M-(C1-e alkylcarbonyl)amino (for example, M-acetyl-M-ethylamino), (4) heterocyclic group (for example, 1- pyrrolidinyl) and (5) alkylcarbonyl (e.g., acetyl, propionyl) optionally having one substituent selected from (a) hydroxy, (5) alkoxy (e.g., methoxy), (c) amino, and (8) Siv alkylamino (for example, isopropylamino);

BZ means hydroxy, optionally having (1) C 1-6 alkyl (e.g., methyl, ethyl) optionally having one C 1-6 alkoxy (e.g.,

ethoxy), or (2) Lower alkyl (e.g., methyl, ethyl) optionally having 1-3 halogen atoms (e.g., a fluorine atom)

And preferably, hydroxy substituted with (1) C 1-6 alkyl (e.g., methyl, ethyl) optionally having one C 1-6 alkoxy (e.g., ethoxy), or (2) C 1-6 alkyl (e.g., methyl, ethyl) optionally having must have 1-3 halogen atoms (for example, a fluorine atom)|;

B" means (1) a hydrogen atom or (2) C 1-6 alkyl (e.g., methyl, ethyl) optionally having one substituent selected from (17) C 3-6 cycloalkyl (e.g., cyclopropyl), (23 C 1-6 aryl (e.g., phenyl) optionally having one C-6 alkoxy (e.g., methoxy), (3) C-6 alkylcarbonyl (e.g., tert-butylcarbonyl), (4) C1-0 arylcarbonyl (e.g., benzoyl ), (5) C-6 alkoxycarbonyl (e.g., ethoxycarbonyl), (6) Arylcarbamoyl group (e.g., phenylcarbamoyl), (7) Heterocyclic group (e.g., 2-pyridyl), (8) S-o aryloxy (e.g., phenoxy ) and (9) carboxy;

BA" means a hydrogen atom or C..is an alkyl group (eg, methyl, ethyl, n-propyl); and

Bhe means a hydrogen atom or C: is an alkyl group (for example, methyl).

IS performance (1"-2)

Compound (I1"), in which

X means O, 5 or M(C-C alkyl) (in particular, M(methyl));

Bg means (A) carbamoyl, optionally having 1 or 2 substituents selected from (1) C 1 -C alkyl (eg, methyl, ethyl, propyl, isopropyl, 2-methylpropyl, 2,2-dimethylpropyl, 1-methylbutyl), which optionally has 1 or 2 substituents selected from (1) halogen atom (eg, fluorine atom), (2) cyano, (3) amino, (4) C.i.v alkylamino (eg, isopropylamino), ( 53 di-Ci-e alkylamino (e.g., dimethylamino, diethylamino) optionally having one hydroxy, (6) Ci-e alkoxycarbonylamino (e.g., tert-butoxycarbonylamino), (7) hydroxy, (8) di-C: 1-alkylcarbamoyl (for example, diethylcarbamoyl), (9 5- - 7-membered cyclic carbamoyl (for example, 1-pyrrolidinylcarbonyl), (10) heterocyclic group (for example, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1- pyrazolyl, 1-imidazolyl, 1-piperidyl, 2-piperidyl, 3-piperidyl, 4-piperidyl, 1-piperazinyl, 1-morpholinyl, 2-pyridyl, 3-pyridyl, 2-tetrahydrofuryl), which optionally has one ( a) hydroxy or (5) C:-C alkyl (for example, met yl, ethyl) optionally having one hydroxy, (11) C1-6 alkoxycarbonyl (eg, ethoxycarbonyl) and (12) C3-6 cycloalkyl (eg, cyclohexyl), (2) C3-6 cycloalkyl (eg, cyclohexyl ), optionally having 1 or 2 substituents selected from (1 amino and (2) hydroxy, (3) C-o aryl (e.g., phenyl), and (4) a heterocyclic group (e.g., 3-pyrrolidinyl, 4- piperidyl, 5-oxido-tetrahydrothiopyran-4-yl), optionally having one substituent selected from (1C-6 alkyl (e.g., methyl), optionally having 1 or 2 substituents selected from (a) Ce-o aryl (e.g., phenyl) and (B) hydroxy, (23 Ce alkylcarbonyl (e.g., methylcarbonyl))y optionally having one substituent selected from (a) C:-e alkylcarbonyloxy (e.g., methylcarbonyloxy) and (B) hydroxy, (3) C 1 -C 6 alkoxycarbonyl (e.g., tert-butoxycarbonyl) and (4) a 5- or b-membered aromatic heterocyclic group (e.g., 4-pyridyl), or (B) a 5- to 7-membered cyclic carbamoyl (for example, 1-pyrrolidinylcarbonyl, 1-pi peridylcarbonyl, 1-

homopiperazinylcarbonyl) optionally having one substituent selected from (1) C alkyl (e.g. methyl, ethyl) optionally having one substituent selected from (a) heterocyclic group (e.g. 1-pyrrolidinyl, benzodioxol-5 -yl) and (p) amino, (2) amino, (3) M-C-C alkyl-M-(C1-e alkylcarbonyl)amino (for example, M-acetyl-M-ethylamino), (4) heterocyclic groups (eg, 1-pyrrolidinyl) and (5) Alkylcarbonyl (eg, acetyl, propionyl) optionally having one substituent selected from (a) hydroxy, (5) Alkoxy (eg, methoxy), (c) amino and (8) C:-alkylamino (eg, isopropylamino);

BZ means hydroxy, optionally having (1) C1-6 alkyl (e.g., methyl, ethyl, n-propyl, i-propyl), optionally having one C1-6 alkoxy (e.g., ethoxy), or (2) C 1-6 alkyl (e.g., methyl, ethyl, n-propyl, i-propyl) optionally having 1-3 halogen atoms (e.g., a fluorine atom)

And preferably, hydroxyl substituted with (1) C 1-6 alkyl (e.g., methyl, ethyl) optionally having one C 1-6 alkoxy (e.g., ethoxy), or (2) C 1-6 alkyl (e.g., methyl, ethyl) optionally having must have 1-3 halogen atoms (for example, a fluorine atom)|;

B" means (1) a hydrogen atom, or (2) C 1-6 alkyl (e.g., methyl, ethyl) optionally having one substituent selected from (17) C 3-6 cycloalkyl (e.g., cyclopropyl), (23 C- o aryl (e.g., phenyl) optionally having (i) 1 or 2 C-6 alkoxy (e.g., methoxy) or (ii) 1 to 3 halogen atoms (e.g., a chlorine atom), (3) C- 6 alkylcarbonyl (e.g., tert-butylcarbonyl), (43 C) arylcarbonyl (e.g., benzoyl), optionally having one halogen atom (e.g., chlorine atom) or C..v. alkoxy (e.g., methoxy), (5) Si -6 alkoxycarbonyl (e.g., ethoxycarbonyl), (6) C-o arylcarbamoyl (e.g., phenylcarbamoyl), (7) heterocyclic group (e.g., 2-pyridyl), (8) C-o aryloxy (e.g., phenoxy), and (9) ) carboxy;

B" means a hydrogen atom or a C. alkyl group (for example, methyl, ethyl, n-propyl); and

Bhe means a hydrogen atom or C: is an alkyl group (for example, methyl).

IS performance (1"-3)

3-ethoxy-6-ethyl-IM-(1-(hydroxyacetyl)piperidin-4-yl|-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H -pyrroloyi3,2-c|Ipyridine-2-carboxamide;

M-P1-"hydroxyacetyl)piperidin-4-yl|-1,6-dimethyl-4-oxo-5-(2-oxo-2-phenylethyl)-3-(2,2,2-trifluoroethoxy)-4, 5-dihydro-1H-pyrrolo|Z,2-c|Ipyridine-2-carboxamide; b-ethyl-M-(P1-(hydroxyacetyl)piperidin-4-yl|-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-3-(2,2,2- trifluoroethoxy) -4,5-dihydro-1H-pyrrolo|3,2-c|Ipyridine-2-carboxamide; or their salt.

When the compound (I) is a salt, examples of such a salt include a metal salt, an ammonium salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, and the like. Preferable examples of metal salts include alkali metal salts such as sodium salt, potassium salt and the like; alkaline earth metal salts, such as calcium salt, magnesium salt, barium salt and the like; aluminum salt and the like. Preferred examples of salts with an organic base include salts with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, M,M'-dibenzylethylenediamine and the like. Preferable examples of inorganic acid salts include hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Preferred examples of organic acid salts include formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid and the like. Preferable examples of salts with a basic amino acid include a salt with arginine, lysine, ornithine and the like, and preferred examples of a salt with an acidic amino acid include a salt with aspartic acid, glutamic acid and the like.

Among them, preference is given to pharmaceutically acceptable salts. For example, if the compound has an acidic functional group, inorganic salts such as alkali metal salts (e.g., sodium salt, potassium salt, etc.), alkaline earth metal salts (e.g., calcium salt, magnesium salt, etc.) may be indicated .) and the like, ammonium salt, etc., and if the compound has a basic functional group, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like can be specified, for example , or salts with organic acids such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like.

Methods of obtaining the compounds of this invention are described below.

In each of the following production methods, if alkylation reaction, amidation reaction (condensation reaction), esterification reaction, reduction reaction, reductive amidation reaction, amination reaction, halogenation reaction, oxidation reaction and the like are carried out, these reactions are carried out according to known methods. Examples of such techniques include the techniques described in

Ogdapis Rhipsiope! Stor Rgeragaiyop5, 2nd ed., Asadetis Rgez5, Ips. (1989), Sotrgepepvime Ogdapis

Tgapvetogtaiop5, MSN Rybiikhpege Ips. (1989) and others, and the like. Reactions of protection and removal of protection are carried out according to known methods, for example, the methods described in Rgoyesiime sgoimrz ip

Ogodapis Zupipev, 3rd ed., Hopp UMieu apa zZopv, Ips. (1999) or by methods similar to them.

Solvents, referred to in general terms, used in the following reactions are described below.

Examples of "alcohols" include methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol and the like.

Examples of "ethers" include diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like.

Examples of "esters" include ethyl acetate, methyl acetate, tert-butyl acetate, and the like.

Examples of "hydrocarbons" include benzene, toluene, xylene, cyclohexane, hexane, pentane, and the like.

Examples of "amides" include M,M-dimethylformamide, M,M-dimethylacetamide, hexamethylphosphoric acid triamide, and the like.

Examples of "halogenated hydrocarbons" include dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, tetrachloroethylene, chlorobenzene, and the like.

Examples of "nitriles" include acetonitrile, propionitrile, and the like.

Examples of "ketones" include acetone, 2-butanone, and the like.

Examples of "organic acids" include formic acid, acetic acid, propionic acid, trifluoroacetic acid, methanesulfonic acid, and the like.

Examples of "aromatic amines" include pyridine, 2,6-lutidine, quinoline, and the like.

Examples of "sulfoxides" include dimethyl sulfoxide and the like.

In the presented production methods, the starting compound and the intermediate compound can be salts. As such salts, salts similar to the salts of the above-mentioned compound (1) can be mentioned.

Compound (I) can be obtained, for example, by Method AI presented below or a method similar to it.

Method A)

Compound (II) is hydrolyzed, and the resulting compound (II) is condensed with an amine, thus compound (1) can be obtained. so x Don V x- with their in X their in? oops oh oh oh oh that

OR) (c) () where is E? means C-C alkyl or benzyl, and other symbols are as defined above.

Examples of C:-is alkyl for K? include methyl, ethyl and the like, preferably ethyl.

Compound (I) can be obtained according to the methods for obtaining compound (ShA) and compound (NAME) given below.

Compound (II) can be converted to compound (II) by hydrolysis under acidic or basic conditions in a solvent, which does not adversely affect the reaction. In particular, if the CC? is benzyl, a catalytic hydrogenation reaction in a solvent can be used, which does not adversely affect the reaction.

Hydrochloric acid, sulfuric acid and the like can be mentioned as the acid used for hydrolysis, and sodium hydroxide, potassium hydroxide, lithium hydroxide and the like as the base. Their number is generally from 1 to 20 molar equivalents, preferably 1-10 molar equivalents, per 1 mol of compound (1).

Examples of the catalyst used for the catalytic hydrogenation reaction include nickel

Rhenium, platinum or palladium oxide, ruthenium, rhodium, iridium and the like on activated carbon, barium sulfate, calcium carbonate and the like. Their amount is generally from 0.01 to 1 molar equivalent, preferably from 0.05 to 0.5 molar equivalent, per 1 mol of compound (II).

Hydrogen, cyclohexene, hydrazine, ammonium formate and the like are used as a source of hydrogen.

Examples of a solvent that does not adversely affect the reaction include ethers, alcohols, hydrocarbons, ketones, nitriles, amides, esters, water, and the like, with alcohols, ethers, and water being preferred.

Two or more types of solvents defined above can be used in a mixture in an acceptable ratio.

The reaction temperature is generally from 0 to 100 "C, preferably 20-60 "C.

The reaction time is generally from 0.5 to 100 hours, preferably 1-48 hours.

The condensation reaction of the compound (II) and the amine can be carried out in a solvent that does not adversely affect the reaction, using, for example, a condensation agent.

The amine used in this reaction can be condensed with the carboxy group of compound (II) to form an "optionally substituted carbamoyl" for K2. Such an amine may be that produced in series, or may be obtained from the corresponding parent compound by a method known to reg 56.

Examples of the condensing agent include carbodiimide (for example, dicyclohexylcarbodiimide (OCCO), water-soluble carbodiimide (MU5CO) and the like), phosphate ester (for example, diethylcyanophosphonate, diethylchlorophosphonate, diphenylphosphoroazide and the like), BOP reagent (1H-benzotriazol-1-yloxytripyrrolidinephosphonium hexafluorophosphate )), 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEBO), carbonyldiimidazole and the like, with preference

MY

The amount of each amine and condensation agent to be used is generally 1 to 10 molar equivalents, preferably 1 to 2 molar equivalents, per 1 mol of compound (II).

Examples of a solvent that does not adversely affect the reaction include ethers, hydrocarbons, ketones, nitriles, amides, esters, and the like, with ethers and amides being preferred. Two or more types of solvents defined above can be used in a mixture in an acceptable ratio.

The reaction temperature is generally from 0 to 100 "C, preferably 20-60 "C.

The reaction time is generally from 0.5 to 100 hours, preferably 1-48 hours.

Among the compounds (IP), the compound (Sha), in which BEZ stands for hydroxy, can be obtained, for example,

By the VI method below or a method similar to it.

ISmethod VI

Compound (M) is reacted with compound (1), and the resulting compound (IM) is treated with a base to give compound (Ха). ho s 2 so sov

N shk Y 2 a 6 0) х b The basis of kh r sov bo on

AD I (A is io; where O is a leaving group, Ke is C-C alkyl, and other symbols are as defined above.

Examples of a leaving group for 0 include a halogen atom (e.g., chlorine, bromine, iodine), optionally halogenated C 1 -alkylsulfonyloxy (e.g., methylsulfonyloxy, ethylsulfonyloxy, trifluoromethylsulfonyloxy), C 1 -o arylsulfonyloxy, optionally having C 1 -c alkyl (eg, benzenesulfonyloxy, 4-toluenesulfonyloxy), methylmercapto, methanesulfonyl and the like, with a halogen atom being preferred.

Examples of C:-e alkyl for KU include methyl, ethyl and the like.

Compound (M) can be obtained according to the methods for obtaining compound (Ma) and compound (Ma-2) given below.

The reaction of compound (M) and compound (1) can be carried out in the presence of a base, if necessary, and in a solvent that does not adversely affect the reaction.

Compound (1) can be produced serially or can be obtained from the corresponding parent compound by a method known to reg 56.

The amount of compound (1) to be used is generally 1 to 20 molar equivalents, preferably 1 to 10 molar equivalents, per 1 mol of compound (M). Examples of the base used as needed include sodium hydride, sodium methoxide, sodium ethoxide, sodium carbonate, sodium bicarbonate, sodium hydroxide, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, and the like. Their amount to be used is generally from 1 to 20 molar equivalents, preferably 2-10 molar equivalents, per 1 mol of the compound (M).

Examples of a solvent that does not adversely affect the reaction include ethers, hydrocarbons, alcohols, amides, esters, and the like, with ethers and amides being preferred. Two or more types of solvents defined above can be used in a mixture in an acceptable ratio.

The reaction temperature is generally from 0 to 100 °C, preferably 20-90 °C.

The reaction time is generally from 0.5 to 100 hours, preferably 1-48 hours.

Compound (IM) can be converted to compound (Sh) using a base in a solvent that does not adversely affect the reaction.

Examples of the base include sodium methoxide, sodium ethoxide, sodium hydroxide, triethylamine and the like, and their amount to be used is generally from 1 to 20 molar equivalents, preferably 2 to 10 molar equivalents, per 1 mol of the compound (IM).

Examples of a solvent that does not adversely affect the reaction include ethers, hydrocarbons, alcohols, amides, esters, and the like, with ethers and amides being preferred. Two or more types of solvents defined above can be used in a mixture in an acceptable ratio.

The reaction temperature is generally from 0 to 100 °C, preferably 20-90 °C.

The reaction time is generally from 0.5 to 100 hours, preferably 1-48 hours.

The compound (M) can be directly converted to the compound (Ха) without the release of the compound (IM).

Among the compounds (III), the compound (PIB), in which EZ is alkoxy, optionally having a substituent(s), can be obtained, for example, by |Method CI below, or by a method similar to it.

SI method

The compound (Xa) is reacted with a halogenated alkyl, sulfuric acid ester, methanesulfonic acid ester, optionally substituted with halogen atom(s), and the like to give the compound (PIB). 9 sok sok x x x-y KU -, ON u S -v s (I - cho

Also) o (Sha) (PIV) wherein BU is alkoxy optionally having substituent(s) and the other symbols are as defined above. "Alkoxy optionally having substituent(s) for K means "hydroxy substituted with alkyl optionally having substituent(s)" included in "hydroxy optionally having substituent(s)" for KZ

The interaction between the compound (Xa) and the halogenated alkyl, sulfuric acid ester, methanesulfonic acid ester, optionally substituted with halogen atom(s), and the like can be carried out in the presence of a base in the solvent, which does not adversely affect the reaction.

The halogenated alkyl, sulfuric acid ester, and methanesulfonic acid ester optionally substituted with halogen atom(s) used in this reaction can alkylate the hydroxyl group of compound (Xa) to form "alukoxy, optionally having substituent(s) for KU.

Such halogenated alkyl, sulfuric acid ester and methanesulfonic acid ester, which is optionally substituted with halogen atom(s), can be produced in series or can be obtained from the corresponding starting compound by a method known to reg" 56.

The amount of halogenated alkyl and similar compounds to be used is generally from 1 to 3 molar equivalents, preferably 1-2 molar equivalents, per 1 mol of compound (Sh). Examples of the base to be used include sodium methoxide, sodium ethoxide, cesium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 1,8-diazabicyclo/5.4.O)undec-7- en (OB) and the like, and their amount to be used is generally from 1 to 5 molar equivalents, preferably from 1 to 3 molar equivalents, per 1 mol of the compound (Sha).

Examples of a solvent that does not adversely affect the reaction include ethers, hydrocarbons, alcohols, ketones, nitriles, amides, esters, and the like, with ethers and amides being preferred. Two or more types of solvents defined above can be used in a mixture in an acceptable ratio.

The reaction temperature is generally from 0 to 100 "C, preferably 20-90 "C.

The reaction time is generally from 0.5 to 100 hours, preferably 1-48 hours.

Among compounds (M), 2-oxonicotinate ester (Ma), in which ring A is a pyridine ring or a condensed pyridine ring, can be obtained, for example, using I (Method BI below) or a method similar to it.

IMethod 0)

The compound (MI) is reacted with malonic acid ester (3) and the hydroxyl group of the obtained compound (MI) is converted to the leaving group C) to obtain the compound (Ma). so o Fo on o so is dz v vya v sov v sok o) (3) ше ш- - | - in" M o v" M o v" M o " g s (MV (M) (Ma) in which K" means a hydrocarbon group, optionally having a substituent(s), and other symbols are as defined above.

As "hydrocarbon group optionally having substituent(s)" for KE" can be specified groups similar to "hydrocarbon group optionally having substituent(s)" for KU.

The interaction of compound (MII) and malonic acid ester (3) can be carried out in the presence of a base in the solvent, which does not adversely affect the reaction.

Malonic acid ester (3) can be produced in series or can be obtained from the corresponding starting compound by the method known to reg" 56.

The amount of malonic acid ester (3) to be used is generally 1 to 2 molar equivalents, preferably 1 to 1.5 molar equivalents, per 1 mol of the compound (MII). Examples of the base used include sodium hydride, sodium methoxide, sodium ethoxide, sodium carbonate, sodium bicarbonate, sodium hydroxide, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, OBO and the like, and the amount to be used is generally from 1 to 10 molar equivalents, preferably 1-5 molar equivalents, per 1 mol of the compound (MI).

Examples of a solvent that does not adversely affect the reaction include ethers, hydrocarbons, ketones, nitriles, amides, and the like, with ethers and amides being preferred. Two or more types of solvents defined above can be used in a mixture in an acceptable ratio.

The reaction temperature is generally from 0 to 100 "C, preferably 0-80 "C.

The reaction time is generally from 0.5 to 100 hours, preferably 1-48 hours.

Conversion of the hydroxyl group of the compound (MI) to the leaving group OO can be carried out, for example, using a halogenating agent and a sulfonylation reagent in a solvent that does not adversely affect the reaction, or without a solvent and, if necessary, in the presence of a base.

Examples of the halogenating reagent include thionyl chloride, phosphoryl chloride, phosphorus pentachloride, phosphorus tribromide, and the like.

The amount of halogenating reagent to be used is generally from 1 to molar equivalents, preferably 2-10 molar equivalents, per 1 mole of compound (MI).

The reaction temperature is generally from 0 to 130 "C, preferably 20-130 "C.

The reaction time is generally from 0.5 to 100 hours, preferably 1-48 hours.

Examples of the sulfonylating agent include trifluoromethanesulfonic acid anhydride, methanesulfonic acid halide, benzenesulfonic acid halide, and the like, and their amount to be used is generally 1 to 2 molar equivalents, preferably 1 to 1.5 molar equivalents, per 1 mol of the compound ( E). Examples of a base that should be used if necessary include triethylamine, diisopropylethylamine, pyridine, 4-

dimethylaminopyridine and the like, and their amount to be used is generally 2 to 5 molar equivalents, preferably 2 to 3 molar equivalents, per 1 mol of the compound (MI).

Examples of a solvent that does not adversely affect the reaction include ethers, hydrocarbons, alcohols, amides, esters, and the like, with ethers and amides being preferred. Two or more types of solvents defined above can be used in a mixture in an acceptable ratio.

The reaction temperature is generally from -10 to 100 "C, preferably 0-60 "C.

The reaction time is generally from 0.5 to 100 hours, preferably 1-48 hours.

The compound (MI), which should be the starting substance in (Method OB), can be synthesized using a known method, for example, the method described in Shdoshgpai oi Neiegosusiis Spetivig, vol. 12, p. 565-572 (1975).

Also, the compound (Ma) can be obtained, for example, using the IC method E|, given below, or a method similar to it.

ISmethod of EI

The hydroxyl group of the compound (MIPI-2) is converted to the leaving group 0, and the resulting compound (MI) is hydrolyzed to obtain the compound (Ma-2). This compound (Ma-2) is reacted with a halogenated hydrocarbon and the like to give compound (Ma). he and 9 o! y v sovy so V sody ey shchi g SHHI m - m - m v m o v m on v mb Ta y 9 I, e (MIP-2) CM) (mMa-2) (ma) in which each symbol is such , as defined above.

The compound (MII) can be obtained according to the synthesis method of the compound (Ma) in the above

IMethods 0). The amount of halogenating reagent and sulfonylating reagent to be used can be increased as necessary.

Hydrolysis of the compound (MI) can be carried out, for example, after replacing the leaving group C) with an acetoxy or alkoxy group or directly under alkaline conditions or acidic conditions in a solvent that does not adversely affect the reaction.

If the leaving group C is replaced by an acetoxy or alkoxy group, for example, sodium acetate, sodium methoxide, sodium ethoxide and the like can be used, and the amount to be used is generally from 1 to 20 molar equivalents, preferably from 1 to 5 molar equivalents equivalents per 1 mol of the compound (MIP).

For direct hydrolysis under acidic conditions, for example, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid and the like can be used as an acid.

For direct hydrolysis under alkaline conditions, for example, an aqueous solution of sodium hydroxide, an aqueous solution of potassium hydroxide, an aqueous solution of lithium hydroxide and the like can be used as a base.

Examples of a solvent that does not adversely affect the reaction include ethers, hydrocarbons, alcohols, ketones, nitriles, amides, water, and the like, with ethers, amides, and water being preferred. Two or more types of solvents defined above can be used in a mixture in an acceptable ratio.

The reaction temperature is generally from 0 to 130 "C, preferably 20-130 "C.

The reaction time is generally from 0.5 to 100 hours, preferably 1-48 hours.

Compound (Ma-2) can be converted to compound (Ma) by reacting compound (Ma-2) with a compound represented by the formula K"-O, where K" is as defined above and C is a leaving group, in a solvent that does not adversely affect the reaction, or without a solvent, if necessary in the presence of a base.

Examples of a leaving group for 0 include a halogen atom (e.g., chlorine, bromine, iodine), an optionally halogenated C 1 -alkylsulfonyloxy group (e.g., methylsulfonyloxy, ethylsulfonyloxy, trifluoromethylsulfonyloxy), C 1 -o arylsulfonyloxy, optionally having C - in alkyl (for example, benzenesulfonyloxy, 4-toluenesulfonyloxy), methyl mercapto, methanesulfonyl and the like, with a preference for a halogen atom.

The amount of the compound represented by the formula K"'-C to be used is generally from 1 to 20 molar equivalents, preferably from 2 to 10 molar equivalents, per 1 mol of the compound (Ma-2g).

Examples of the base to be used if necessary include triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, sodium hydride, potassium carbonate, cesium carbonate, potassium t-butoxide, sodium t-butoxide and the like, with sodium t-butoxide being preferred. and their amount to be used is generally from 2 to 5 molar equivalents, preferably from 2 to 3 molar equivalents, per 1 mole of the compound (mMa-g).

Preferably, tetrabutylammonium bromide or the like is added to the reaction mixture.

Examples of a solvent that does not adversely affect the reaction include ethers, hydrocarbons, alcohols, amides, esters and the like, preferably ethers and amides. Two or more types of solvents defined above can be used in a mixture in an acceptable ratio.

The reaction temperature is generally from -10 to 100 "C, preferably 0-60 70.

The reaction time is generally from 0.5 to 100 hours, preferably 1-48 hours.

The compound (MIPI-2), which is the starting substance in Method E|, can be synthesized using a known method, for example, the method described in Doigpai oi Ogdapis Spetivig, vol. 46, p. 3040-3048 (1981).

Among compounds (I), compound (Ia) and compound (IB) can be obtained, for example, by (Method PI below or a method similar to it.

RI method

Compound (IB) and compound (Ia) can be obtained from compound (Ic) using the reaction according to Method EI. sia 1 in x x x x x X to Z to Z to z

In | t in Kk | and Kk Kk | po Kk vu m ta v oto (a mo (s) I (c) (c) in which each symbol is as defined above.

The conversion of compound (Ic) to compound (IB) can be carried out according to the reaction in which compound (Ma-2) is obtained from compound (MIII) in (Method E)Y.

The reaction of converting compound (IB) into compound (Ia) can be carried out according to the reaction in which compound (Ma) is obtained from compound (Ma-2) in |Method E|.

The compound (Ic) can be prepared according to the method for the preparation of the compound (Isa) and the compound (Ib) given below.

Among the compounds (Is), the compound (Isa), in which KZ is hydroxy, and the compound (ISB), in which KZ is alkoxy, optionally having a substituent(s), (shown as BU in the following formula (Isb)) can be obtained, for example, using |Method (3) below, or a method similar to it.

Method c)

The compound (Isa) and the compound (Isb) can be obtained from the compound (MI!) by means of reactions according to the IS method AI, |Method VI and |(Method SI. sov v? v? a x x x v sov v h an re h on re h r

TK | and: | se | he mb ta shcha Ma you MU and you MU Zo

SM) (ta) (Isa) (sb) in which each symbol is as defined above.

The conversion of the compound (MI) into the compound (Sha") can be carried out according to (Method VI.

The conversion of compound (Isa!) to compound (Isa) can be carried out according to (Method A).

The conversion of compound (Isa) to compound (Ic) can be carried out according to

SI method.

Also, the compound (IB) can be obtained, for example, by Method NO below, or a method similar to it.

There is NO method

Among the compounds (IB), the compound (IB) in which BE is alkoxy, optionally having a substituent(s), (shown as B? in the following formula (IB) can be obtained by removing P" from the compound (Id) , where BZ means alkoxy optionally having a substituent(s) (shown as EZ in the following formula (Id) and

IN? means phenacyl, optionally having a substituent(s), methoxymethyl, 4-methoxybenzyl or 2,4-dimethoxybenzyl (shown as K" in the following formula (Id)) from the number of compounds (Ia). в в" х х в' there is what x in c': sh-o x in? ----32 in M 9) in" M o) and: and 1 vd (IB) in which KE" means phenacyl, optionally having a substituent(s), methoxymethyl, 4-methoxybenzyl or 2,4-dimethoxybenzyl , and other symbols are as defined above.

When K" is phenacyl, optionally having a substituent(s), the conversion of compound (Id) to compound (IB) can be carried out, for example, in the presence of a metal such as zinc and the like under acidic conditions in a solvent that does not adversely affect the reaction. The amount of zinc to be used is generally 1 to 20 molar equivalents, preferably 1 to 10 molar equivalents, per 1 mol of compound (14). As an acid, hydrochloric acid, sulfuric acid and the like are used.

Examples of a solvent that does not adversely affect the reaction include ethers, hydrocarbons, alcohols, ketones, nitriles, amides, water, and the like, with ethers, amides, and water being preferred. Two or more types of solvents defined above can be used in a mixture in an acceptable ratio.

The reaction temperature is generally from 20 to 120 "C, preferably 20-100 "C.

The reaction time is generally from 0.5 to 100 hours, preferably 1 to 24 hours.

When B" is methoxymethyl, the conversion of compound (4) to compound (IB) can be carried out under acidic conditions in a solvent that does not adversely affect the reaction. As an acid, hydrochloric acid, sulfuric acid and the like can be used.

Examples of a solvent that does not adversely affect the reaction include ethers, hydrocarbons, alcohols, ketones, nitriles, amides, water, and the like, with ethers, amides, and water being preferred. Two or more types of solvents defined above can be used in a mixture in an acceptable ratio.

The reaction temperature is generally from 0 to 120 "C, preferably 20-60 "C.

The reaction time is generally from 0.5 to 100 hours, preferably 1 to 24 hours.

When K" is 4-methoxybenzyl, the conversion of compound (I4) to compound (IB) can be carried out under strongly acidic conditions in a solvent that does not adversely affect the reaction. As an acid, trifluoroacetic acid, trifluoromethanesulfonic acid and the like can be used. in this case, anisole can be used as a cationic scavenger in a total amount of 1 to 20 molar equivalents, preferably 1-5 molar equivalents, per 1 mol of compound (I).

Examples of a solvent that does not adversely affect the reaction include ethers, hydrocarbons, alcohols, ketones, nitriles, amides and the like, preferably ethers and amides. Two or more types of solvents defined above can be used in a mixture in an acceptable ratio.

The reaction temperature is generally from 0 to 120 "C, preferably 20-60 "C.

The reaction time is generally from 0.5 to 100 hours, preferably 1-24 hours.

When K" is 2,4-dimethoxybenzyl, the conversion of compound (Id) to compound (IB) can be carried out in the presence of an oxide such as cerium (IM) diammonium nitrate (CAM), 2,3-dichloro-5,6b-dicyano -1,4- benzoquinone (000) and the like in a solvent that does not adversely affect the reaction.

The amount of anthum oxide to be used is generally from 1 to 20 molar equivalents, preferably from 1 to 5 molar equivalents, per 1 mol of compound (Id).

Examples of a solvent that does not adversely affect the reaction include ethers, hydrocarbons, alcohols, ketones, nitriles, amides, water, and the like, with ethers, nitriles, amides, and water being preferred. Two or more types of solvents defined above can be used in a mixture in an acceptable ratio.

The reaction temperature is generally from 0 to 120 "C, preferably 20-60 "C.

The reaction time is generally from 0.5 to 100 hours, preferably 1 to 24 hours.

In addition, the compound (Xa) can be obtained, for example, using |Method I| given below or a method similar to it.

Method I)

Compound (MB) is reacted with compound (4) to obtain compound (Pa). altsov and sozh

But x-y a - СО жЖ -72- ОН k А The basis (А - о шка за (MB) (Ша) in which 9 is the leaving group and the other symbols are as defined above.

Examples of a leaving group for C include groups similar to the leaving group for the aforementioned C) with a preference for a halogen atom.

Compound (4) may be a commercially available reagent or may be synthesized by a method known to reg 56.

A compound (MB), for example, a derivative of b-amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate and the like, which should be the starting compound in |Method |, can be synthesized using known method, for example, the method described in Shdoshigpa! oh Spetis! bosieiu oi darap, volume 46, p. 3849-3853 (1973). For example, a derivative of 2-mercapto-4-oxo-1,4-dihydroquinoline-3-carboxylate and the like can be synthesized using a known method, for example, the method described in

Choshigpai oi Neiegosusiis Spetivigu, volume 27, p. 839-843 (1990).

The interaction between compound (MB) and compound (4) can be carried out in the presence of a base in the solvent, which does not adversely affect the reaction.

The amount of compound (4) to be used is generally from 1 to 3 molar equivalents, preferably 1-2 molar equivalents, per 1 mol of compound (MB). Examples of the base include sodium methoxide, sodium ethoxide, sodium carbonate, sodium hydrogencarbonate, sodium hydroxide, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine and the like, and the amount to be used is generally 2 to 5 molar equivalents, preferably 2 -3 molar equivalents, per 1 mole of the compound (Mb).

Examples of a solvent that does not adversely affect the reaction include ethers, hydrocarbons, alcohols, ketones, nitriles, amides, water, and the like, with ethers, amides, and water being preferred. Two or more types of solvents defined above can be used in a mixture in an acceptable ratio.

The reaction temperature is generally from 20 to 120 "C, preferably 20-100 "C.

The reaction time is generally from 0.5 to 100 hours, preferably 1 to 24 hours.

The compound included in the scope of this invention can also be obtained by applying to compound (I) means known in the art for the introduction of substituents and the transformation of functional groups.

Conventional methods can be used to convert substituents. For example, conversion to a carboxy group by hydrolysis of an ester, conversion to a carbamoyl group by amidation of a carboxy group, conversion to a hydroxymethyl group by reduction of a carboxy group, conversion to an alcohol compound by reduction or alkylation of a carbonyl group, reductive amination of a carbonyl group, oximation of a carbonyl group, acylation, carbamidation, sulfonylation can be cited. or alkylation of an amino group, substitution and amination of an active halogen with an amine, amination of a nitro group by reduction, alkylation of a hydroxy group, substitution and amination of a hydroxy group, and the like. If in the process of introducing substituents and transforming functional groups, a reactive substituent is present that causes an undesirable reaction, if necessary, a protective group is introduced into the reactive substituent in advance by means known to the reg ze, and the protective group is removed by means known to the reg ze after the completion of the target reaction, thus obtaining such a compound that is within the scope of this invention.

In the above production method, if the original compound or the compound of the present invention has an amino group, a carboxyl group, a hydroxyl group, or a mercapto group as a substituent, a protective group commonly used in peptide chemistry and the like can be introduced into this group. The protecting group may be removed in accordance with conventional methods at any stage in each scheme.

Compound (I) can be isolated and purified by means known to reg 56, such as phase transfer, concentration, solvent extraction, fractionation, liquid conversion, crystallization, recrystallization, chromatography and the like. If the compound (I) is obtained in the form of a free compound, it can be converted to the desired salt by the method known in Reg 56 or by a method analogous to it. Conversely, if the compound is obtained in the form of a salt, it can be converted into the free form or other desired salt by a method known in the art or by a method analogous thereto.

Compound (I) can be used as a prodrug. Prodrugs of compound (I) mean a compound that is transformed into compound (I) by a reaction under the action of an enzyme, gastric acid, etc. in the physiological conditions of the body, that is, a compound that is transformed into compound (I) by oxidation, reduction, hydrolysis, etc. under the action of an enzyme, a compound that turns into compound (I) by hydrolysis, etc. under the action of stomach acid, and the like.

Prodrugs of compound (I) can be a compound obtained by subjecting the amino group in compound (I) to acylation, alkylation or phosphorylation (for example, a compound obtained by subjecting the amino group in compound (I) to eicosanoylation, alanylation, pentylaminocarbonylation, (5-methyl- 2-oxo-1,3-dioxolen-4-ylmethoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation or tert-butylation); a compound obtained by subjecting the hydroxyl group in compound (I) to acylation, alkylation, phosphorylation or boration (for example, a compound which is obtained by subjecting the hydroxyl group in compound (I) of the present invention to acetylation, palmitoylation, propanoylation, pivaloylation, succinylation, fumarylation, alanylation or dimethylaminomethylcarbonylation); a compound which is obtained by subjecting the carboxyl group in compound (I) to esterification or amidation (for example, compound , which is obtained by subjecting the carboxyl group in compound (I) to ethyl esterification, phenyl esterification, carboxymeth esterification, dimethylaminomethylesterification, pivaloyloxymethylesterification, ethoxycarbonyloxyethylesterification, phthalidylesterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methylesterification, cyclohexyloxycarbonylethylesterification or methylamidation) and the like.

Any of these compounds can be obtained from compound (I) by a method known to reg 56.

A prodrug of compound (I) can also be a compound that is converted to compound (I) under physiological conditions, such as the conditions described in IMACONIM on KAINATZA (OemeIortepi oi Rpaptaseshiisa!5), Volume 7, rezidp oi MoiIescshev5, pp. 163-198 , Publ. NICOKAUM ZNOTEM (1990).

If the compound (I) has an isomer such as an optical isomer, a stereoisomer, a positional isomer, a rotational isomer and the like, any isomer and a mixture thereof are covered by the compound (I). For example, if compound (I) has an optical isomer, the optical isomer isolated from the racemate is also within the range of compound (I). Such isomers can be obtained as independent products by methods of synthesis or means of separation (concentration, solvent extraction, column chromatography, recrystallization, and the like), known in reg 56.

Compound (I) may be crystalline, and both a single crystal and a mixture of crystals are encompassed by compound (II). Crystals may be obtained by crystallization according to crystallization methods known to reg 56.

Compound (I) can be a co-crystal.

Compound (I) may be a hydrate, non-hydrate, solvate or non-solvate, both of which are covered by compound (I) and the like.

A compound labeled with an isotope (eg, 2H, UZN, 120, 355, 125|, etc.) is also covered by compound (1).

The compound (I) of the present invention or its salt or its prodrug (sometimes abbreviated as "compound of the present invention" in the presented description) interacts, for example, with the human 5ito protein and changes its spatial structure, in connection with which the formation of a complex with the protein involved in signal transduction in the cytoplasm is inhibited and the signal transduction system of the hedgehog (Neddepod) is inhibited. Alternatively, the compound of the present invention interacts with the human Zto protein and directly inhibits the formation of a complex of the human Zto protein with a protein involved in the Neddepod signal transduction system in the cytoplasm, in accordance with the 3th signal transduction system

Neddeipod is inhibited. Alternatively, the compound of the present invention interacts with the 5to site of a protein, such as a phosphorylation site and the like, which is modified by a protein involved in the Neddeipod signal transduction system, thus the modification such as 5to phosphorylation and the like is inhibited, and the Neddeipod signal transduction system is also inhibited is inhibited

Inhibition of the Neddepod signal transduction system can be measured, for example, by quantifying the decrease in the expression level of a reporter gene linked to a protein sequence in the direction of expression of the Si binding site, based on fluorescence intensity according to

Experimental Example 1. Alternatively, it can be measured by quantifying the expression of SIIII-1 mRNA in a cell extract by quantitative PCR and the like. To detect a decrease, a compound that inhibits Neidepod signaling targets is used, which can be confirmed, for example, by binding fluorescently labeled cyclopamine and the test compound to cells expressing 30, measuring the level of fluorescence of the cells and comparing the values with the values without the addition of the test compound .

Accordingly, a compound of the present invention is useful as a 5to inhibitor in mammals (eg, mice, rats, hamsters, rabbits, cats, dogs, cattle, sheep, monkeys, humans, and the like). The compound of the present invention is used as a pharmaceutical agent such as an agent for the prevention or treatment of diseases that are likely to be affected by Zto, for example, cancer (for example, colorectal cancer (for example, colon cancer, rectal cancer, anal canal cancer, hereditary colorectal cancer , hereditary nonpolyposis colorectal cancer, gastrointestinal stromal tumor, etc.), lung cancer (for example, non-small cell lung cancer, small cell lung cancer, malignant mesothelioma, etc.), mesothelioma, pancreatic cancer (for example, ductal cancer pancreas, pancreatic tumor, etc.), pharyngeal cancer, larynx cancer, esophageal cancer, stomach cancer (for example, papillary adenocarcinoma, mucinous adenocarcinoma, glandular squamous cell cancer, etc.), duodenal cancer, small intestine cancer , breast cancer (for example, invasive ductal carcinoma, ductal carcinoma IP 5Zysh, inflammatory breast cancer etc.), ovarian cancer (for example, epithelial ovarian cancer, extragonadal gonocytoma, ovarian gonocytoma, low-potential malignant ovarian tumor, etc.), testicular tumors, prostate cancer (for example, hormone-dependent prostate cancer, hormone- independent prostate cancer, etc.), liver cancer (for example, hepatocellular carcinoma, primary liver cancer, extrahepatic bile duct cancer, etc.), thyroid cancer (for example, medullary thyroid cancer, etc. ), kidney cancer (for example, renal cell carcinoma, transitional cell cancer of the renal pelvis and ureter, etc.), uterine cancer (for example, cervical cancer, uterine body cancer, uterine sarcoma, etc.), tumors brain (for example, medulloblastoma, glioma, pineal astrocytoma, piloid astrocytoma, diffuse astrocytoma, anaplastic astrocytoma, pituitary adenoma, etc.), retinoblastoma, skin cancer (for example, basal cell carcinoma, malignant melanoma, etc.), sarcomas (for example, rhabdomyosarcomas, l eyomyosarcoma, soft tissue sarcoma, etc.), malignant bone tumors, bladder cancer, blood cancer (for example, multiple myeloma, leukemia, malignant lymphoma, Hodgkin's disease, chronic myeloproliferative diseases, etc.), unknown cancer primary localization, etc. |, cancer cell growth inhibitor, cancer metastasis inhibitor, cell apoptosis promoter, etc... Among them, the compound of the present invention is effective, for example, for brain tumors, skin cancer, lung cancer, cancer pancreas, bile duct cancer, prostate cancer, esophageal cancer, stomach cancer, colorectal cancer, sarcoma and breast cancer. In particular, the compound of the present invention is effective for glioma, medulloblastoma, basal cell tumors, small cell lung cancer, pancreatic cancer, bile duct cancer, prostate cancer, esophageal cancer, gastric cancer, colorectal cancer, rhabdomyosarcoma and breast cancer.

The compound of the present invention can be administered orally or parenterally as a single agent or in admixture with a pharmaceutically acceptable carrier.

The dosage form of the compound of the present invention for oral administration can be, for example, in the form of a tablet (including a sugar-coated tablet, a film-coated tablet), a pill, a granule, a powder, a capsule (including soft capsules and microcapsules), a syrup, an emulsion , suspensions and the like, and the dosage form for parenteral administration can be, for example, in the form of an injection, injectable agent, instillation, suppositories, etc. In addition, it is effective for the manufacture of a dosage form of prolonged release to combine compounds with a suitable base (for example, with a polymer of butyric acid, a polymer of glycolic acid, a copolymer of butyric acid and glycolic acid, a mixture of a polymer of butyric acid and a polymer of glycolic acid, a polyglycerol ester of a fatty acid, etc.).

As a method of obtaining the compound of the presented invention in the dosage form indicated above, a method of obtaining that is commonly used in this field is known. When the above-mentioned dosage form is obtained, appropriate amounts of excipients such as excipient, binder, disintegrant, lubricating agent, sweetener, surfactant, suspending agent, emulsifier and the like are added as necessary, which are usually are used in this field.

When the compound of the present invention is obtained in the form of a tablet, for example, it can be obtained by adding an excipient, a binder, a disintegrant, a lubricating agent and the like, and when a pill or granule is obtained, they can be obtained by adding an excipient, a binder, disintegrant and the like. When a powder or capsule is obtained, it can be obtained by adding an excipient and the like, when a syrup is obtained, it can be obtained by adding a sweetener and the like, and when an emulsion or suspension is obtained, it can be obtained by adding a suspending agent, a surfactant, emulsifier and the like.

Examples of the excipient include lactose, sucrose, glucose, starch, sucrose, microcrystalline cellulose, licorice powder, mannitol, sodium bicarbonate, calcium phosphate, calcium sulfate, and the like.

Examples of binders include 5-10 wt. for liquid starch paste, 10-20 mabs. 95% gum arabic solution or gelatin solution, 1-5 wt.95% tragacanth solution, carboxymethylcellulose solution, sodium alginate solution, glycerin and the like.

Examples of the disintegrant include starch, calcium carbonate, and the like.

Examples of the lubricating agent include magnesium stearate, stearic acid, calcium stearate, refined talc and the like.

Examples of the sweetener include glucose, fructose, invert sugar, sorbitol, xylitol, glycerin, simple syrup, and the like.

Examples of surfactants include sodium lauryl sulfate, polysorbate 80, sorbitol monofatty acid ester, polyoxyl 40 stearate, and the like.

Examples of the suspending agent include gum arabic, sodium alginate, sodium carboxymethylcellulose, methylcellulose, bentonite, and the like.

Examples of the emulsifier include gum arabic, tragacanth, gelatin, polysorbate 80 and the like.

In addition, when the compound of the present invention is obtained in the form of the dosage form mentioned above, if necessary, suitable amounts of dye, preservative, flavoring agent, corrigent, stabilizer, thickener and the like, typically used in this field, may be added.

As an injection, intravenous injection, intradermal injection, intramuscular injection, instillation, and the like can be mentioned, and as a sustained release dosage form, an iontophoretic transdermal agent and the like can be mentioned.

Such injections are obtained using methods known as such, or by dissolving, suspending or emulsifying the compound of the present invention in a sterilized aqueous or oily medium. As an aqueous medium for injection, physiological saline, isotonic solutions containing glucose or other auxiliary agents (for example, O-sorbitol, O-mannitol, sodium chloride and the like) and the like can be specified and can be used in combinations with suitable solubilizing agents such as alcohols (eg, ethanol), polyalcohols (eg, propylene glycol, polyethylene glycol), nonionic surfactants (eg, polysorbate 80, HCO-50), and the like. As the oil medium, there may be mentioned sesame oil, soybean oil and the like, which may be used in combination with solubilizing agents such as benzyl benzoate, benzyl alcohol and the like. In addition, buffering agents (e.g. phosphate buffer, sodium acetate buffer), sedative agents (e.g. benzalkonium chloride, procaine hydrochloride and the like), stabilizers (e.g. human serum albumin, polyethylene glycol and the like), preservatives (e.g. , benzyl alcohol, phenol and the like) and the like. The ampoule is usually filled with the resulting injection medium.

While the content of the compound of the present invention in the pharmaceutical agent of the present invention varies depending on the form of the pharmaceutical formulation, it generally ranges from about 0.01 to 100 wt. 95, preferably from about 2 to 85 wt. 95, more preferably from about 5 to 70 wt. 95, regarding the entire recipe.

While the content of the excipient in the pharmaceutical agent of the present invention varies depending on the form of the pharmaceutical formulation, it generally ranges from about 1 to 99.9 wt. 95, preferably from about 10 to 90 wt. 95, regarding the entire recipe.

The compound of the present invention is stable and low-toxic and can be used safely. While the daily dose varies depending on the condition and body weight of the patients, the type of compound, the route of administration, etc., in the case of, for example, oral administration to patients for the treatment of cancer, the daily dose for an adult (with a body weight of about 60 kg) is approximately 1-1000 mg, preferably about 3-300 mg, more preferably about 10-200 mg of the active ingredient (a compound of the present invention), which can be given in one dose or given in 2 or 3 parts during the day.

When a compound of the present invention is administered parenterally, it is generally administered in the form of a liquid (eg, injection). While the dose varies depending on the subject of administration, target organ, symptom, route of administration, etc., it is, for example, from about 0.01 mg to about 100 mg, preferably from about 0.01 to about 50 mg, more preferably from about 0.01 to about 20 mg, in the form of an injection, per 1 kg of body weight, which is preferably administered by intravenous injection.

The compound of the present invention can be used simultaneously with other medicinal products. In particular, the compound of the present invention can be used together with medicines, such as hormonal therapeutic agents, chemotherapeutic agents, immunotherapeutic agents, pharmaceutical agents that inhibit the action of cell growth factors or cell growth factor receptors, etc. Hereinafter, drugs that can be used in combination with the compound of the present invention are referred to as accompanying drugs.

Examples of "hormonal therapeutic agents" include phosphestrol, diethylstilbestrol, chlorotrianisen, medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, cyproterone acetate, danazol, allylestrenol, gestrinone, mepartricin, raloxifene, ormeloxifene, leformeloxifene, anti-estrogens (eg, tamoxifen citrate, toremifene citrate , etc.), pill formulations, mepitiostan, testrolactone, aminoglutethimide, agonists of I H-KN (for example, goserelin acetate, buserelin, leuprorelin, etc.), droloxifene, epithiostanol, ethinyl estradiol sulfonate,

aromatase inhibitors (for example, fadrozole hydrochloride, anastrozole, retrozole, exemestane, vorozol, formestane, etc.), anti-androgens (for example, flutamide, bicartamide, nilutamide, etc.), 5o-reductase inhibitors (for example ) retinoid and drugs that slow down the metabolism of retinoid (for example, liarozol, etc.), thyroid hormone and 005 (Ogyd

Oeiimegu Zuziet) drugs (drug delivery systems) and the like.

Examples of "chemotherapeutic agents" include alkylating agents, antimetabolites, anticancer antibiotics, herbal anticancer agents, and the like.

Examples of "alkylating agents" include nitrous mustard, nitrous mustard M-oxide hydrochloride, chlorambutyl, cyclophosphamide, ifosfamide, thiotepa, carbochion, improsulfan tosylate, busulfan, nimustine hydrochloride, mitobronitol, melphalan, dacarbazine, ranimustine, estramustine sodium phosphate, triethylenemelamine, carmustine, lomustine, streptozocin, pipobroman, etoglucide, carboplatin, cisplatin, miboplatin, nedaplatin, oxaliplatin, altretamine, ambamustine, dibrospidium hydrochloride, fotemustine, prednimustine, pumitepa, ribomustine, temozolomide, treosulfan, trophosphamide, zinostatin stimalamer, adozelesin, cystemustine, bizelesin, their 005 (Abomination of Oeiiimegu

Zuziet) drugs (drug delivery systems) and the like.

Examples of "antimetabolites" include mercaptopurine, b-mercaptopurine riboside, thioinosine, methotrexate, pemetrexed, enocitabine, cytarabine, cytarabine oxphosphate, ancitabine hydrochloride, 5-EO drugs (eg, fluorouracil, tegafur, ORT, doxyfluredine, carmofur, halocitabine, emitefur, capecitabine and similar), aminopterin, nelzarabine, calcium leucovorin, tabloid, butocin, calcium folinate, calcium levofolinate, cladribine, emitefur, fludarabine, gemcitabine, hydroxycarbamide, pentostatin, pyritrexim, idoxyridine, mitoguason, thiazophrin, ambamustine, bendamustine, their O5 preparations and others like them.

Examples of "anticancer antibiotics" include actinomycin-O, actinomycin-C, mitomycin-C, chromomycin-AZ, bleomycin hydrochloride, bleomycin sulfate, peplomycin sulfate, daunorubicin hydrochloride, doxorubicin hydrochloride, aclarubicin hydrochloride, pyrarubicin hydrochloride, epirubicin hydrochloride, neocarcinostatin, mithramycin, sarcomycin, carcinophyllin, mitotane, zorubicin hydrochloride, mitoxantrone hydrochloride, idarubicin hydrochloride, their 005 (Ogyd Oeiimegu Zuhket) preparations (drug delivery systems) and the like.

Examples of "anticancer agents of plant origin" include etoposide, etoposide phosphate, vinblastine sulfate, vincristine sulfate, vindesine sulfate, teniposide, paclitaxel, docetaxel, vinorelbine, their 0O5 preparations, and the like.

Examples of "immunotherapeutic agents (ITAs)" include pizibanil, crestin, sozofiran, lentinan, ubenimex, interferons, interleukins, macrophage colony-stimulating factor, granulocyte colony-stimulating factor, erythropoietin, lymphotoxin, BSO vaccine, Sogupebasiegist ragmite, levamisole, polysaccharide K, procodazole, anti- STI A4 antibody and the like.

Examples of "cell growth factors" in "pharmaceutical agents that inhibit the action of cell growth factors or cell growth factor receptors" include any substances that promote cell proliferation, which are usually peptides having a molecular weight of no more than 20,000 that are capable of its activity at low concentrations by binding to the receptor, including (1) ESE (epidermal growth factor) or substances that exhibit essentially the same activity as ESE

(eg, TOKoh, etc.), (2) insulin or substances that have essentially the same activity as insulin (eg, insulin, ISE (insulin-like growth factor)-1, ISE-2, etc.). Y, (3) ESE (fibroblast growth factor) or substances that show essentially the same activity as ESE I, for example, acid ESE, basic ESE, KOE (keratinocyte growth factor), ESE-10, etc.), (4) other cell growth factors (for example, C5E (colony-stimulating factor), EPO (erythropoietin), 1-2 (interleukin-2), MOB (nerve growth factor), ROSE (platelet growth factor), TOEr (transforming growth factor p ), NOE (hepatocyte growth factor), MESE (vascular endothelial growth factor), heregulin, angiopoietin, etc. |.

Examples of "cell growth factor receptors" include any receptor capable of binding to the growth factors mentioned above, including the ECE receptor, the heregulin receptor (NEKZ, etc.), the insulin receptor, the IEE receptor-1, the IEE-2 receptor , ECE-1 receptor or EOBE-2 receptor, MESE receptor, angiopoietin receptor (Tie2, etc.), ROSE receptor, etc.

As "pharmaceutical agents that inhibit the action of cell growth factors or cell growth factor receptors" use ESE inhibitor, TOEs inhibitor, heregulin inhibitor, insulin inhibitor, inhibitor

ISE, ESE inhibitor, KOBE inhibitor, C5BE inhibitor, EPO inhibitor, 1-2 inhibitor, MOB inhibitor, inhibitor

ROSRE, TOERp inhibitor, NOBE inhibitor, MESE inhibitor, angiopoietin inhibitor, ECE receptor inhibitor, NEK2 inhibitor, NEKIA4 inhibitor, insulin receptor inhibitor, ICE-1 receptor inhibitor, ICE-2 receptor inhibitor, ECE receptor-1 inhibitor, ECE receptor inhibitor- 2, ESE receptor-3 inhibitor, BOR receptor-4 inhibitor, MESBE receptor inhibitor, Tie-2 inhibitor, ROSBE receptor inhibitor,

ABI inhibitor, Kai inhibitor, RI TZ inhibitor, c-KIi inhibitor, 5gs inhibitor, PKS inhibitor, TC inhibitor, inhibitor

Kei, tTOR inhibitor, Ayigog inhibitor, RIC inhibitor, MEK (MEKT/2) inhibitor, MET inhibitor, SOC inhibitor, AKI inhibitor, EKK inhibitor and the like. More specifically, anti-MESE antibody (Bevacizumab, etc.), anti-NEK2 antibody (Trastuzumab, Pertuzumab, etc.), anti-ESEK antibody (Cetuximab, Panitumumab, Matuzumab, Nimotuzumab, etc.) are used. anti-MESEK antibody, anti-NOE antibody,

Imatinib mesylate, Erlotinib, Gefitinib, Sorafenib, Sunitinib, Dasatinib, Lapatinib, Vatalanib, 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-b-methoxy-7-|3-(1-pyrrolidinyl )upropoxy|quinazoline (A2O-2171),

Lestaurtinib, Pazopanib, Canertinib, Tandutinib, 3-(4-bromo-2,6-difluorobenzyloxy)-5-(3-I(4-(1-pyrrolidinyl)butylureido|isothiazole-4-carboxamide (SR-547632), Axitinib) , M-(3,3-dimethyl-2,3-dihydro-1H-indol-b-yl)-2-(pyridin-4-ylmethylamino)pyridine-3-carboxamide (AMO-706), Nilotinib, /-6 -(4-(4-ethylpiperazin-1-ylmethyl)phenyl|-M-(1(A)-phenylethyl|-7H-pyrrolo|2,3-4|pyrimidin-4-amine (AEE-788),

Vandetanib, Temsirolimus, Everolimus, Enzastaurin, M-I(4-(4-(4-methylpiperazin-1-yl)-6-(3-methyl-1H-pyrazol-5-ylamino)pyrimidin-2-ylsulfanyl|Iphenyl cyclopropanecarboxamide (UK-680), phosphoric acid 2-(M-(3-(4-(5-(M-(3-fluorophenyl)carbamoylmethyl-1H-pyrazol-3-ylamino)quinazolin-7-yloxy|propyl) |/-

M-ethylamino|ethyl ester (AO-1152), 4-(3-chloro-7-(2,6-difluorophenyl)-5H-pyrimidoi5,4- a|((2Ibenzazepin-2-ylamino|benzoic acid (MIM- 8054), M-(2-methoxy-5-(KE)-2-(2,4,6-trimethoxyphenyl)vinylsulfonylmethyl|phenyl|glycine sodium salt (OM-1910Ma), 4-I(8-cyclopentyl-7( 8)-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-ylamino|-3-methoxy-M-(1-methylpiperidin-4-yl/benzamide (VI-2536), 5-(4-bromo-2-chlorophenylamino)-4-fluoro-1-methyl-1H-benzimidazole-b-carbohydroxamic acid 2-hydroxyethyl ester (А2О0-6244), M-(2(В),З- dihydroxypropoxy|-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benzamide (RO-0325901), Everolimus (KAOOOT) and the like.

In addition to the drugs mentioned above, I -asparginase, aceglaton, procarbazine hydrochloride, protoporphyrin-cobalt complex salt, mercury hematoporphyrin-sodium, topoisomerase I inhibitors (for example, irinotecan, topotecan, etc.), topoisomerase IHI inhibitors (for example , sobuzoxan, etc.), differentiation inducers (for example, retinoid, vitamin 0, etc.), other inhibitors of angiogenesis (for example, humagillin, shark extract, COX-2 inhibitor, etc.), o- blockers (e.g. tamsulosin hydrochloride, etc.), bisphosphonic acids (pamidronate, zoledronate, etc.), thalidomide, 5 azacitidine, decitabine, proteasome inhibitor (e.g., bortezomib, etc., antitumor antibody, such such as anti-CO20 antibody and the like, toxin-labeled antibody and the like.

The joint use of the compound of the present invention and the accompanying medicinal product leads, for example, to the following excellent results (1) the dose can be reduced compared to the separate use of the compound of the presented invention or the accompanying medicinal product, (2) the combination medicinal product with the compound of the presented invention can be selected depending depending on the condition of the patients (moderate, complex, etc.), (3) a longer period of treatment can be established, (4) a long-term therapeutic effect can be achieved, (5) a synergistic effect can be achieved with the combined use of the compound of the present invention and the accompanying medicinal tool

In the present description, the compound of the present invention and the accompanying drug used in combination are referred to herein as the "combination agent of the present invention."

When the combined agent of the present invention is used, the time of administration of the compound of the present invention and the accompanying drug is not limited, and the compound of the present invention and the accompanying drug can be administered to the subject simultaneously or at intervals. The dose of the accompanying drug can be determined according to the clinically established dose, and can be appropriately selected depending on the subject to whom it is administered, the route of administration, the disease, the combination, etc.

Examples of the route of administration for the combined use of the compound of the present invention and the accompanying medicinal product include the following methods: (1) The compound of the present invention and the accompanying medicinal product are produced at the same time, obtaining a single preparation, which is then administered. (2) The compound of the present invention and the accompanying medicinal product are produced separately, obtaining two types of preparations that are administered simultaneously by the same route of administration. (3) The compound of the presented invention and the accompanying medicinal product are produced separately, obtaining two types of preparations that are administered by the same route of administration but at different times. (4) The compound of the present invention and the accompanying drug are produced separately, obtaining two types of drugs that are administered simultaneously but by different routes of administration. (5) The compound of the present invention and the accompanying medicine are produced separately, obtaining two kinds of drugs that are administered by different routes at different times (for example, the compound of the present invention and the accompanying medicine are administered in this order, or in the reverse order). The dose of the accompanying medicinal product is determined in accordance with its clinical dose, and the ratio of the compound of the present invention and the accompanying medicinal product is determined depending on the subject, route of administration, type of disease, symptom, combination, etc. For example, when the subject the subject is a person, the accompanying drug is used in the amount of 0.01-100 (mass parts), relative to 1 mass part of the compound of the presented invention.

The combined agent of the present invention has low toxicity and, for example, the compound of the present invention and/or the above-mentioned accompanying drug can be mixed, according to a method known in the art, with a pharmaceutically acceptable carrier, obtaining pharmaceutical compositions such as tablets (including a tablet with sugar coated, film-coated tablet), powders, granules, capsules (including soft capsules), solutions, injections, suppositories, sustained-release agents, and the like that can be safely administered orally or parenterally (e.g., topically, rectally , in a vein, etc.). the injection can be administered intravenously, intramuscularly, subcutaneously or intra-organally, or directly into the tumor.

As a pharmacologically acceptable carrier that can be used for the preparation of the combined agent of the present invention, one that is similar to the above-mentioned pharmacologically acceptable carriers that can be used for the preparation of the pharmaceutical agent of the present invention can be specified. When necessary, the above-mentioned excipients that can be used to prepare the pharmaceutical agent of the present invention, such as preservatives, antioxidants, dyes, sweeteners, adsorbents, wetting agents, etc., can also be used in appropriate amounts.

The compositional ratio of the compound of the present invention to the accompanying medicinal product in the combined agent of the present invention can be appropriately set depending on the subject of administration, the route of administration, the type of diseases, etc.

For example, the content of the compound of the present invention in the combined agent of the present invention varies depending on the dosage form and is usually about 0.01 to 100 wt. 96, preferably from about 0.1 to 50 wt. 95, also preferably from about 0.5 to 20 wt. 95, based on the recipe.

The content of the concomitant medicinal product in the combined agent of the present invention varies depending on the dosage form and usually ranges from about 0.01 to 90 wt. 95, preferably from about 0.1 to 50 wt. 95, also preferably from about 0.5 to 20 wt. 95, based on the recipe.

The content of excipients in the combined agent of the present invention varies depending on the dosage form and usually ranges from about 1 to 99.99 wt. 95, preferably from about 10 to 90 wt. 95, based on the recipe.

When the compound of the present invention and the accompanying drug are prepared separately, this content may be the same.

These dosage forms can be prepared using essentially known methods that are commonly used in manufacturing processes.

For example, the compound of the present invention and the accompanying drug can be obtained in the form of an aqueous injection together with a dispersing agent (for example, Tmeep 80 (manufactured by Ayaz

Romdeg, 05), HSO 60 (produced by Mikko Speptis!5), polyethylene glycol, carboxymethyl cellulose, sodium alginate, hydroxypropyl methyl cellulose, dextrin, etc.), stabilizer (for example, ascorbic acid, sodium pyrosulfite, etc.), surface active substance (for example,

Polysorbate 80, macrogol, etc.), a solubilizer (for example, glycerin, ethanol, etc.), a buffering agent (for example, phosphoric acid or its alkali metal salt, citric acid or its alkali metal salt, etc. etc.), an isotonic agent (for example, sodium chloride, potassium chloride, mannitol, sorbitol, glucose, etc.), a pH adjusting agent (for example, hydrochloric acid, sodium hydroxide, etc.), a preservative (for example, ethyl paraoxybenzoate, benzoic acid, methylparaben, propylparaben, benzyl alcohol, etc.), a dissolution aid (for example, concentrated glycerin, meglumine, etc.), a solubilizing agent (for example, propylene glycol, sucrose, etc.), a sedative ( e.g. glucose, benzyl alcohol, etc.) and the like, or may be dissolved, suspended or emulsified in vegetable oil such as olive oil, sesame oil, cottonseed oil, corn oil, etc., or solubilizing age nti, such as propylene glycol or the like to obtain an oil injection, whereby the injection is provided.

In addition, to obtain a dosage form for oral administration, an excipient (for example, lactose, sucrose, starch, etc.), a disintegrating agent (for example, starch, calcium carbonate, etc.) can be added to the compound of the present invention or the accompanying medicinal product. etc.;), binding agent (for example, starch, gum arabic, carboxymethyl cellulose, polyvinylpyrrolidone, hydroxypropyl cellulose, etc.), lubricating agent (for example, talc, magnesium stearate, polyethylene glycol 6000, etc.) and the like , and the mixture may be pressed into a mold and, if necessary, according to techniques known in the art, an enteric coating or a sustained release coating may be applied to the molded product for taste masking purposes. As a coating agent can be used, for example, hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, Tween 80, Pluronic E68, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, Eudragit (copolymer of methacrylic acid/acrylic acid, produced by Kopt, OE ), pigment (for example, iron oxide red, titanium dioxide, etc.) and the like. The dosage form for oral administration can be in any form, immediate release dosage form and sustained release dosage form.

In addition, the compound of the present invention or the accompanying medicinal product can be obtained in the form of an oily or aqueous, solid, semi-solid or liquid suppository by techniques known in the field, by mixing them with an oil substrate, an aqueous substrate or a hydrogel substrate. As the oil substrate mentioned above, it is possible to mention, for example, glycerides of higher fatty acids and, for example, cocoa butter, Uitepsol (manufactured by Oupatie Mobei

Sotrapu, Septapu) etc.), medium-chain fatty acid glycerides (e.g. Migliols (by Oupatie Maubet! Sotrapu, Septapu) etc.) or vegetable oils (e.g. sesame oil, soybean oil, seed oil cotton, etc.) and the like. In addition, the aqueous substrate includes, for example, polyethylene glycol and propylene glycol and the like, and the hydrogel substrate includes, for example, natural rubbers, cellulose derivatives, vinyl polymers, acrylic acid polymers, and the like.

Sustained-release microcapsules and the like are indicated as the above-mentioned sustained-release dosage form. Sustained-release microcapsules can be prepared by a method generally known in the art, for example, the method shown below in (21.

Preferably, the compound of the present invention is converted into a dosage form for oral administration, such as a solid dosage form (eg, powder, granule, tablet, capsule) or a dosage form for rectal administration, such as a suppository, etc. A dosage form for oral administration is particularly preferred.

The accompanying medicine can be obtained in the form of the dosage form described above, depending on the type of medicine.

GP Injectable dosage form and its preparation

Preference is given to the injectable dosage form obtained by dissolving the compound of the present invention or the accompanying medicinal product in water. This injectable dosage form may contain a benzoate and/or a salicylate.

The injectable dosage form is obtained by dissolving the compound of the present invention or accompanying medicinal product and, optionally, benzoate and/or salicylate in water.

As the above-mentioned benzoic and salicylic acid salts, alkali metal salts such as sodium and potassium salts and the like, alkaline earth metal salts such as calcium and magnesium salts and the like, ammonium salts, meglumine salts, salts with organic bases such as trometamol and the like.

The concentration of the compound of the present invention or the accompanying drug in the injectable dosage form is from about 0.5 to 50 wt/o 956, preferably from about 3 to 20 wt/o 95. The concentration of benzoate and/or salicylate is from 0.5 to 50 wt/o 95, preferably from C to wt/o 95.

The injection dosage form of the presented invention can contain auxiliary substances that are usually used in injection, for example, a stabilizer (for example, ascorbic acid, sodium pyrosulfite, etc.), a surface-active substance (for example, Polysorbate 80, macrogol etc.), solubilizer (for example, glycerin, ethanol, etc.), buffering agent (for example, phosphoric acid and its alkali metal salt, citric acid and its alkali metal salt, etc.), isotonic agent (for example, sodium chloride, potassium chloride, etc.), dispersing agent (for example, hydroxypropyl methylcellulose, dextrin), pH adjusting agent (for example, hydrochloric acid, sodium hydroxide, etc.), preservative (for example, ethyl parahydroxybenzoate, benzoic acid, etc.), dissolution assistant (for example, concentrated glycerin, meglumine, etc.), solubilizing agent (for example, propylene glycol, sucrose, etc.), sedative (for example, glucose, benzyl alcohol and etc.) and the like. These excipients are added in the quantitative ratio usually used in injectable dosage forms.

The advantage is that the pH of the injectable dosage form can be adjusted to 2-12, preferably to 2.5-8.0 by adding a pH adjusting agent.

The injectable dosage form is obtained by dissolving the compound of the present invention or the accompanying medicinal product and, optionally, the benzoate and/or salicylate and, if necessary, the above-mentioned excipients in water. These components can be dissolved in any order and can be accordingly dissolved according to the standard method of obtaining injectable dosage forms.

The aqueous solution for injection may preferably be heated, alternatively, for example, subjected to sterilization filtration, sterilization at high pressure and high temperature, etc., to obtain an injectable dosage form, as in the case of obtaining a conventional injectable dosage form.

The advantage is that the aqueous solution of the injection dosage form can be subjected to sterilization at high pressure and high temperature, for example, at 100-1219C for 5-30 minutes.

In addition, the dosage form can be in the form of a solution with antibacterial activity for the possibility of using it as a multi-dose form and for distributed administration. (2 Pharmaceutical form of prolonged release or pharmaceutical form of immediate release and their receipt

A preferred sustained-release dosage form consists of a core that contains a compound of the present invention or an accompanying drug, optionally coated with a layer of a coating agent such as a water-insoluble substance or a swellable polymer. For example, a sustained-release dosage form for oral administration in a once-daily dosage form is preferred.

The water-insoluble substance used in the coating agent includes, for example, cellulose ethers such as ethyl cellulose, butyl cellulose, etc., cellulose esters such as cellulose acetate, cellulose propionate, etc., polyvinyl esters such as such as polyvinyl acetate, polyvinyl butyrate, etc., acrylic acid/methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylate/cinnamoethyl methacrylate/aminoalkyl methacrylate copolymers, polyacrylic acid, polymethacrylic acid, methacrylic acid alkylamide copolymers, poly(methyl methacrylate) polymethacrylate, polymethacrylamide, aminoalkylmeth poly(methacrylic anhydride), glycidyl methacrylate copolymer, in particular, polymers based on acrylic acid, such as Eudragit (manufactured by Kopt RIagta), such as Eudragit K5-100, VI-100, v5-300, VI-z00, VI-RO, V5 -PO (ethyl acrylate/methyl methacrylate/trimethyl chloride methacrylate/ethylammonium copolymer), Eudragit ME-300 (methyl methacrylate/ethyl rylate copolymer) etc., hydrogenated oils such as hydrogenated castor oil (e.g. Ishbii Lah (manufactured by Egeip Sogrohaiog) and the like), waxes such as carnauba wax, glycerol fatty acid ester, paraffin etc. etc., polyglycerol and fatty acid esters, and the like.

As a swellable polymer, polymers having a dissociable acid group and exhibiting pH-dependent swelling are preferred, and polymers having a dissociable acid group exhibiting slight swelling in an acidic environment such as stomach and swell intensely in a neutral environment such as the small and large intestines.

Examples of such a polymer that has an acid group capable of dissociation and exhibits pH-dependent swelling include a polymer of cross-linked polyacrylic acid, such as Carbomer 93АР, 940, 941, 974Р, 980, 1342, etc., polycarbophil and calcium polycarbophil ( all productions of VE Sooaisn),

NimizuuaKo 103, 104, 105, 304 (all productions of U/ako Riga Spetisai! Ipaiviiiev, Tsa.) and similar.

The coating agent used in the sustained release dosage form may also contain a hydrophilic substance.

As a hydrophilic substance can be specified, for example, polysaccharides that may contain a sulfate group, such as pullulan, dextrin, alkali metal alginate, etc., polysaccharides that have a hydroxyalkyl or carboxyalkyl group, such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose and etc., methyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, etc.

The content of water-insoluble substance included in the coating agent of the sustained-release dosage form is from about 30 to about 90 95 (w/w), preferably from about 35 to about 80 95 (w/w), more preferably from about 40 to about 75 95 (w/w), the swellable polymer content is from about 3 to about 30 95 (w/w), preferably from about 3 to about 15 95 (w/w). The coating agent may also contain a hydrophilic substance, in which case the amount of hydrophilic substance included in the coating agent is from about 50 to about 95 (w/w) or less, preferably from about 5 to about 40 95 (w/w), more preferably from about 5 to about 35 95 (w/w). As used herein, 90 (w/w) means 95 by weight based on the composition of the coating agent obtained by removing the solvent (e.g., water, lower alcohols such as methanol, ethanol, etc.) .

Below is an example of the manufacture of a sustained-release dosage form by obtaining a core containing drugs, followed by applying a solution of a coating layer to the resulting core, obtained by dissolving a water-insoluble substance when heated, or by swelling a polymer and the like, or by dissolving or dispersing such substances in a solvent.

I. Obtaining a core containing a medicinal product

The shape of the drug-containing core coated with a coating agent (hereinafter sometimes simply referred to as the core) is not particularly limited, and is preferably formed of particles such as granules or fine particles.

When the core consists of granules or small particles, it has an average particle size preferably from about 150 to about 2000 μm, more preferably from about 500 to about 1400 μm.

The core can be obtained using a conventional method. For example, the drug is mixed with a suitable excipient, binder, disintegrating agent, lubricating agent, stabilizer, etc., and then subjected to wet extrusion granulation, fluid granulation, or the like to obtain a core.

The drug content of the core is from about 0.5 to about 95 95 (w/w), preferably from about 5.0 to about 80 95 (w/w), more preferably from about 30 to about 70 95 (w/w ).

As an excipient contained in the core, saccharides such as sucrose, lactose, mannitol, glucose, etc., starch, crystalline cellulose, calcium phosphate, corn starch, etc. are used. Among them, preference is given to crystalline cellulose and corn starch.

As a binder, for example, polyvinyl alcohol, hydroxypropyl cellulose, polyethylene glycol, polyvinylpyrrolidone, Pluronic E68, gum arabic, gelatin, starch, etc. are used. As a disintegrating agent, for example, calcium carboxymethylcellulose (ЕСО505), croscarmellose sodium (Ас-Ои-50И), cross-linked polyvinylpyrrolidone (Crospovidone), low-substituted hydroxypropyl cellulose (I-HPS), etc. are used. Among them, preference is given to hydroxypropyl cellulose, polyvinylpyrrolidone and low-substituted hydroxypropyl cellulose. As a lubricating agent and anticoagulant, for example, talc, magnesium stearate and its inorganic salts are used, and as a lubricating agent, for example, polyethylene glycol, etc. are used. Acids such as tartaric acid, citric acid, succinic acid, fumaric acid, maleic acid, etc. are used as stabilizers.

In addition to the method described above, the core can also be obtained using other methods, for example, a roll granulation method, a method using a coating apparatus, a fluidized bed coating method, and a melt granulation method, in which the drug or drug mixture with an excipient, a lubricating agent and the like, parts are added to the particles of the inert carrier as the core of the core by sputtering a binder dissolved in a suitable solvent such as water, a lower alcohol (eg, methanol, ethanol and the like) or the like. As an inert carrier particle, for example, particles made from sucrose, lactose, starch, crystalline cellulose, and waxes can be used, and preferably, the average particle size is from about 100 microns to about 1500

MKM.

To separate the drug contained in the core from the coating agent, the surface of the core can be coated with a protective material. The above-described hydrophilic substances and water-insoluble substances are used as a protective material. Polyethylene glycol and polysaccharides having a hydroxyalkyl or carboxyalkyl group, more preferably hydroxypropylmethylcellulose and hydroxypropylcellulose, are used as a protective material. The protective material may contain an acid stabilizer such as tartaric acid, citric acid, succinic acid, fumaric acid, maleic acid and the like, and lubricating agents such as talc and the like.

When a protective material is used, its amount in the coating is from about 1 to about 15 95 (w/w), preferably from about 1 to about 10 95 (w/w), more preferably from about 2 to about 8 95 (w/w ), based on the mass of the nucleus.

The protective material may be applied by a conventional coating technique, and in particular, the protective material may be applied to the core by sputtering, for example, by a fluidized bed technique, a coating technique, etc.

I. Coating the core using a coating agent

A coating is applied to the core obtained in the above-mentioned stage I, using a solution of the agent for applying the coating layer, obtained by dissolving the water-insoluble substance described above and the pH-dependent swellable polymer and the hydrophilic substance during heating, either by dissolving them or by dispersing them in a solvent with receiving a dosage form of prolonged release.

As a method of applying a coating to the core using a solution of an agent for applying a coating layer, for example, sputtering and the like are mentioned.

The ratio of a water-insoluble substance capable of swelling a polymer or a hydrophilic substance in a solution of a coating agent is suitably chosen within the limits of the quantities of the corresponding components containing the coating layer.

The amount of coating agent is from about 1 to about 90 95 (w/w), preferably from about 5 to about 50 95 (w/w), more preferably from about 5 to about 3595 (w/w), based on mass of the core (excluding the amount of the layer of protective material).

As a solvent for the coating agent solution, water or an organic solvent can be used alone or as a mixture thereof. When a mixture is used, the ratio of water to organic solvent (water/organic solvent: mass ratio) may vary from 1 to 100 95, and preferably from 1 to about 30 95. The organic solvent is not particularly limited as long as it dissolves the water-insoluble substance and, for example, lower alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol, n-butyl alcohol and the like, lower alkane such as acetone, acetonitrile, chloroform, methylene chloride and the like can be used. Among them, preference is given to lower alcohols, and particular preference is given to ethyl alcohol and isopropyl alcohol. Water and a mixture of water with an organic solvent are preferably used as a solvent for the coating agent solution. In this case, if necessary, an acid such as tartaric acid, citric acid, succinic acid, fumaric acid can also be added to the coating agent solution. , maleic acid and the like, with the aim of stabilizing the coating solution.

The sputter coating process can be carried out by a conventional coating technique, and specifically it can be carried out by applying a coating agent solution to the core using a fluidized bed coating technique, a spray coating technique or the like . In this case, if necessary, a lubricating agent such as talc, titanium oxide, magnesium stearate, calcium stearate, light anhydrous silicon dioxide and the like, and a plasticizer such as glycerol fatty acid ester, hydrogenated castor oil, triethyl citrate may also be added. , cetyl alcohol, stearyl alcohol and the like.

After coating with a coating agent, if necessary, an antistatic agent such as talc and the like may be added.

The immediate release dosage form can be liquid (solution, suspension, emulsion, etc.) or solid (particle, pill, tablet, etc.). As the immediate release dosage form, oral administration and parenteral administration such as injection and the like can be used, and oral administration is preferred.

An immediate release dosage form, in addition to the active drug ingredient, may typically contain carriers, excipients, and excipients (hereinafter sometimes referred to as excipients) commonly used in the pharmaceutical industry. The excipient used is not particularly limited as long as it is an excipient commonly used in the pharmaceutical industry. For example, as an excipient for a solid dosage form for oral administration, lactose, starch, corn starch, crystalline cellulose (Amise! РНИ1О1, manufactured by Azaipi Kazei Sogrogayop and the like), powdered sugar, granulated sugar, mannitol, light anhydrous silica gel, magnesium carbonate, calcium carbonate, I-cysteine and the like, and corn starch and "mannitol" are preferred. Any of these excipients may be used alone or in combination of two or more. The amount of excipient is, for example, from about 4.5 to about 99.4 wt/wt 95, preferably from about 20 to about 98.5 wt/wt 95, more preferably from about 30 to about 97 wt/wt 95, based on total weight of the immediate release dosage form.

The drug content of the immediate release dosage form may be suitably selected in the range of from about 0.595 to about 95 wt/wt 95, preferably from about 195 to about 60 wt/wt 95 of the total weight of the immediate release dosage form.

If the immediate release dosage form is a solid dosage form for oral administration, it, in addition to the components described above, contains a disintegrating agent. As the mentioned disintegrating agent are used, for example, calcium carboxymethyl cellulose (ECO 505, produced by SoyoKi Uakiyip), croscarmellose sodium (for example, Asiizhoi, produced by Azapiya

Kazei Sogrogayop), crospovidone (for example, KoPdop Si, manufactured by VABE), low-substituted hydroxypropyl cellulose (Zpip-Ei5y Spetis! So., Tsa.), carboxymethyl starch (Maibshapi Kadaki

K.K.), sodium carboxymethylurochmal (Ehogiar, manufactured by Kitiga BZapduo), partially pregelatinized starch (ROZ, manufactured by Azai Kazei Sogrogayop) and the like and, for example, disintegrating agents that disintegrate the granule by absorbing water upon contact with water can be used, swelling or forming a channel between the active component and the excipient included in the core. Any of these disintegrating agents may be used alone or in combination of two or more. The amount of disintegrating agent used can be suitably selected depending on the type and total amount of drug used, release profile and the like and, for example, the amount is from about 0.05 to about 30 wt/wt 95, preferably from about 0.5 to approximately 15 wt/wt 95 based on the total weight of the immediate release dosage form.

If the immediate release dosage form is a solid dosage form for oral administration, it may, in addition to the components described above, contain excipients commonly used in a solid dosage form. As such an auxiliary substance, a binding agent (for example, sucrose, gelatin, powdered gum arabic, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, polyvinylpyrrolidone, pullulan, dextrin, and the like), a lubricating agent (polyethylene glycol, magnesium stearate, talc, light anhydrous) is used silica gel (for example, Aerosil (Mirrop

Aegosia)), surfactant (for example, anionic surfactants such as sodium alkyl sulfate and the like, nonionic surfactants such as polyoxyethylene fatty ester and polyoxyethylene sorbitol fatty ester, polyoxyethylene castor oil derivatives and the like), dyes (for example, resinous dye, caramel, iron oxide red, titanium oxide, riboflavins), if necessary, flavor correctors (for example, sweeteners, flavorings and the like), adsorbent, preservative, wetting agent, antistatic and the like. In addition, an organic acid such as tartaric acid, citric acid, succinic acid, fumaric acid or the like may also be added as a stabilizer.

Hydroxypropyl cellulose, polyethylene glycol and polyvinylpyrrolidone and the like are preferably used as the above-mentioned binder.

The pharmaceutical form of immediate release can be obtained on the basis of the standard technology of obtaining medicines by mixing the above-mentioned components, if necessary, additional grinding of the mixture, and its formation. The aforementioned mixing is carried out by commonly used methods, for example, mixing, grinding, etc. In particular, if an immediate-release dosage form is obtained, for example, in the form of particles, it can be obtained in the same way as the above-mentioned method of obtaining a core for a sustained-release dosage form, by mixing the components using a vertical blender, a universal plasticizer for grinding the mixture (production Naia Tekko5po), fluidized bed granulator EO-55 (manufactured by Romgeh Sogrohaiyop), etc., followed by granulation of the mixture by wet extrusion granulation or fluidized bed granulation, etc.

The immediate-release dosage form and the sustained-release dosage form thus obtained may be mixed as such or together with acceptable pharmaceutical excipients and the like by a conventional method, then may be administered simultaneously or administered in combination at some time interval, or they can be made into a single oral dosage form (eg, granule, particle, tablet, capsule, and the like) as is or made into a single oral dosage form, respectively, together with pharmaceutical excipients. It is also assumed that both dosage forms can be made in the form of granules or small particles and placed in a separate capsule for use as a dosage form for oral administration.

IZI Sublingual, buccal or dosage form that quickly disintegrates in the oral cavity, and its preparation

Sublingual, buccal or orally disintegrating agents may be in the form of a solid dosage form such as a tablet or the like. or may be in the form of an oral mucosal patch (film).

As a sublingual, buccal, or rapidly disintegrating agent in the oral cavity, a dosage form containing a compound of the present invention or an accompanying drug and excipient is preferred. The dosage form may also contain excipients such as a lubricating agent, an isotonic agent, a hydrophilic carrier, a water-dispersible polymer, a stabilizer, and the like. In addition, in order to improve absorption and increase bioavailability, the dosage form may also contain p-cyclodextrin or pD-cyclodextrin derivatives (for example, hydroxypropyl-p-cyclodextrin and the like).

Lactose, sucrose, UO-mannitol, starch, crystalline cellulose, light anhydrous silica gel and the like are mentioned as the excipient mentioned above. As a lubricating agent, magnesium stearate, calcium stearate, talc, colloidal silica gel and the like are indicated, and in particular, magnesium stearate and colloidal silica gel are preferred. As an isotonic agent, sodium chloride, glucose, fructose, mannitol, sorbitol, lactose, sucrose, glycerol, urea and the like are mentioned, and mannitol is particularly preferred. Examples of the hydrophilic carrier include swellable hydrophilic carriers such as crystalline cellulose, ethyl cellulose, cross-linked polyvinylpyrrolidone, light anhydrous silica, silicic acid, dicalcium phosphate, calcium carbonate, and the like, and in particular, crystalline cellulose (e.g., microcrystalline cellulose and the like). Resins (for example, gum tragacanth, gum arabic, guar gum), alginates (for example, sodium alginate), cellulose derivatives (for example, methyl cellulose, carboxymethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose), gelatin, water-soluble starch are indicated as polymers capable of dispersing in water. , polyacrylic acids (for example,

Carbomer), polymethacrylic acid, polyvinyl alcohol, polyethylene glycol, polyvinylpyrrolidone, polycarbophil, ascorbic acid, palmitates and the like, and in particular, preference is given to hydroxypropyl methylcellulose, polyacrylic acid, alginate, gelatin, carboxymethylcellulose, polyvinylpyrrolidone and polyethylene glycol. Hydroxypropylmethylcellulose is particularly preferred. As a stabilizer, cysteine, thiosorbitol, tartaric acid, citric acid, sodium carbonate, ascorbic acid, glycine, sodium sulfite and the like are indicated, and citric acid and ascorbic acid are particularly preferred.

A sublingual, buccal, or rapidly disintegrating agent in the oral cavity may be prepared by mixing a compound of the present invention or an accompanying drug and an excipient using a method known in the art. In addition, if necessary, the auxiliary substances defined above, such as a lubricating agent, an isotonic agent, a hydrophilic carrier, a water-dispersible polymer, a stabilizer, a dye, a sweetener, a preservative, and the like, can be mixed. Sublingual, buccal or means that quickly disintegrate in the oral cavity are obtained by mixing the components described above at the same time or with some time interval, then the mixture is pressed into tablets. To ensure suitable hardness, it is permissible, if necessary, to moisten the components before and after tableting using a solvent such as water, alcohol and the like, followed by drying to obtain the product.

When preparing an oral mucosal patch (film), the compound of the present invention or the accompanying drug and the water-dispersible polymer described above (mainly hydroxypropyl cellulose, hydroxypropyl methyl cellulose), excipients and the like are dissolved in a solvent such as water and the like and then a film is cast from the resulting solution. In addition, excipients such as plasticizer, stabilizer, antioxidant, preservative, color, buffering agent, sweetener, and the like may also be added. To give the film the necessary elasticity, a glycol such as polyethylene glycol, propylene glycol and the like can be added, or to increase the adhesion of the film to the surface of the oral mucosa, a bioadhesive polymer (for example, polycarbophil, carbopol) can also be added. When casting, the solution is poured onto a non-adhesive surface, sprayed to a uniform thickness (preferably from about 1000 microns) using a spraying device, such as a squeegee knife, etc., then the solution is dried to form a film. The advantage is that the film obtained in this way is dried at room temperature or when heated, and then cut into pieces of the desired plane.

As a preferred dosage form that rapidly disintegrates in the oral cavity, for example, fast-disintegrating solid preparations consisting of a solid mesh base containing a compound of the present invention or an accompanying drug and a water-soluble or water-diffusible carrier that is inert with respect to the compound of the present invention are indicated of the invention or accompanying medicinal product. The mesh base is formed by sublimation of a solvent from a solid composition containing a solution of a compound of the present invention or an accompanying drug in a suitable solvent.

An advantage is that the composition, which rapidly disintegrates in the oral cavity, contains a matrix-forming agent and a secondary component, in addition to the compound of the present invention or the accompanying drug.

Examples of the matrix-forming agent include gelatins, dextrins, animal or vegetable proteins from soybeans, wheat, psyllium seeds, and the like; rubber substances such as gum arabic, guar gum, agar, xanthan and the like; polysaccharides; alginic acids; carboxymethyl cellulose; carrageenans; dextran; pectins; synthetic polymers such as polyvinylpyrrolidone and the like; substances that are derivatives of the gelatin-gum arabic complex and the like. In addition, the matrix-forming agent includes saccharides such as mannitol, dextrose, lactose, galactose, trehalose and the like; cyclic saccharides such as cyclodextrin and the like; inorganic salts such as sodium phosphate, sodium chloride, aluminum silicate and the like; amino acids having from 2 to 12 carbon atoms, such as glycine, 1-alanine, I-aspartic acid, I-glutamic acid, GI-hydroxyproline, I-isoleucine, I-leucine, I-phenylalanine and the like.

One or more matrix-forming agents may be included in the solution or suspension prior to curing. Matrix-forming agents may be present in addition to the surfactant, or may be present in the absence of the surfactant. Matrix-forming agents not only provide the formation of a matrix, but also help support the diffusion of a compound of the present invention or an accompanying drug in a solution or suspension.

The composition may contain secondary components, such as a preservative, an antioxidant, a surfactant, a thickener, a colorant, a pH adjusting agent, a flavoring agent, a sweetener, a flavoring agent, and the like. As a suitable dye, red, black and yellow iron oxides, EO 4. C dyes such as EO 8. C Vice 2 and EO 48. C Kea 40 and the like, produced by BEIIYi5 5, are noted.

Emegaga. Examples of suitable flavors include mint, raspberry, licorice, orange, lemon, grapefruit, caramel, vanilla, cherry, grape, and combinations thereof. Examples of suitable pH adjusting agents include citric acid, tartaric acid, phosphoric acid, hydrochloric acid and maleic acid. Examples of suitable sweeteners include aspartame, acesulfame

K and thaumatin and the like. Examples of suitable flavoring agent include sodium bicarbonate, ion exchange resin, cyclodextrin including compounds, adsorbents and microencapsulated apomorphine.

The dosage form contains a compound of the present invention or an accompanying drug in an amount usually from about 0.1 to about 50 wt. 9o, preferably from about 0.1 to about 30 wt. 95 and, preferably, are dosage forms (such as the above sublingual, buccal, and the like) that can provide 90 95 or more dissolution (in water) of a compound of the present invention or an accompanying drug in a time range of about 1 up to about 60 minutes, preferably from about 1 minute to about 15 minutes, more preferably from about 2 minutes to about 5 minutes, and dosage forms that rapidly disintegrate in the oral cavity and that disintegrate within about 1 to about 60 seconds, preferably from about 1 to about 30 seconds, more preferably from about 1 to about 10 seconds, after entering the oral cavity.

The content of the above excipient is from about 10 to about 99 wt. 95, preferably from about 30 to about 90 wt. 95, based on the total weight of the dosage form.

The content of VD-cyclodextrin or derivative RD-cyclodextrin is from about 0 to about 30 wt. 9o, based on the total weight of the dosage form. The content of the lubricating agent is from about 0.01 to about 10 wt. 95, preferably from about 1 to about 5 wt. 95, based on the total weight of the dosage form. The content of the isotonic agent is from about 0.1 to about 90 wt. 95, preferably from about 10 to about 70 wt. 95, based on the total weight of the dosage form. The content of the hydrophilic carrier is from about 0.1 to about 50 wt. 95, preferably from about 10 to about 30 wt. 95, based on the total weight of the dosage form. The content of water-dispersible polymer is from about 0.1 to about wt. 95, preferably from about 10 to about 25 wt. 95, based on the total weight of the dosage form. The content of the stabilizer is from about 0.1 to about 10 wt. 95, preferably from about 1 to about 5 wt. 95, based on the total weight of the dosage form. In addition, the dosage form defined above, if necessary, may contain auxiliary substances, such as dye, sweetener, preservative and the like.

The dosage of the combined agent of the present invention varies depending on the type of compound of the present invention, age, body weight, condition, drug form, administration method, administration time period and the like and, for example, for a cancer patient (adult, with body weight: about 60 kg), the combination agent is administered intravenously at a dose of from about 0.01 to about 1000 mg/kg/day, preferably from about 0.01 to about 100 mg/kg/day, more preferably from about 0.1 to about 100 mg /kg/day, in particular, from about 0.1 to about mg/kg"/day, especially from about 1.5 to about 30 mg/kg/day, per compound of the present invention or accompanying drug, respectively, one once or several times a day. Of course, since, as defined above, the dosage may vary according to various conditions, sometimes amounts less than the dosage defined above may be sufficient, and in addition, sometimes amounts higher than in the specified intervals.

The amount of the accompanying medicinal product can be set to any value, provided that side effects do not occur. The daily dose per accompanying medicinal product varies depending on the complexity of the disease, age, sex, body weight, differences in sensitivity of the subject to whom treatment is prescribed, treatment period, interval and characteristics, formulation, type of pharmaceutical preparation, activity of components, etc. .p., and is not particularly limited, and the amount of the drug in the case of oral administration, for example, is usually from about 0.001 to 2000 mg, preferably from about 0.01 to 500 mg, more preferably from about 0.1 to 100 mg per 1 kg of the mammal's body weight, which is usually administered 1 to 4 times a day.

When administering the combined agent of the present invention, the compound of the present invention may be administered after the administration of the accompanying drug or the accompanying drug may be administered after the administration of the compound of the present invention, although they may be administered simultaneously. When they are administered at certain intervals, the intervals vary depending on the effectiveness of the ingredient administered, the form of the drug and the route of administration and, for example, when the accompanying drug is first administered, the compound of the present invention can be administered at a time interval of from 1 minute to 3 days. preferably from 10 minutes to 1 day, more preferably from 15 minutes to 1 hour after administration of the accompanying medicinal product. When the compound of the present invention is first administered, the accompanying drug may be administered 1 minute to 1 day, preferably 10 minutes to 6 hours, more preferably 15 minutes to 1 hour after the administration of the compound of the present invention.

In a preferred method of administration, for example, the accompanying drug, which is formulated into a dosage form for oral administration, is administered orally at a daily dose of about 0.001-200 mg/kg, and after about 15 min. the compound of the present invention, which is formulated into a dosage form for oral administration, is administered in a daily dose of approximately 0.005 to 100 mg/kg.

In addition, a compound of the present invention or a combined agent of the present invention may be used concurrently with drug-free therapy. More specifically, the compound of the present invention or the combined agent of the present invention can be combined with non-drug therapy such as (1) surgery, (2) hypertensive chemotherapy using angiotensin II and the like, (3) gene therapy, (4) thermotherapy, ( 5) cryotherapy, (6) laser burning, (7) radiotherapy, etc.

For example, by using the compound of the present invention or the combined agent of the present invention before or after surgery, etc., or before or after the combined treatment of two or three of them, effects such as preventing the emergence of resistance, prolonging relapse-free survival, suppressing cancer metastasis or recurrence, prolongation of life and the like.

In addition, it is possible to combine treatment with a compound of the present invention or a combination agent of the present invention with adjuvant therapy (i) administration of antibiotics (eg, p-lactam type such as pansporin and the like, macrolide type such as clarithromycin and the like.) to treat complications due to various infectious diseases, (ii) administration of high-calorie infusions, amino acid preparations or general vitamin preparations to compensate for insufficient nutrition, (ii) administration of morphine to relieve pain, (im) administration of a pharmaceutical agent to mitigate side effects, such as nausea, vomiting , anorexia, diarrhea, leukopenia, thrombocytopenia, decrease in hemoglobin concentration, hair loss, hepatopathy, nephropathy, CVD syndrome, fever and the like and (m) administration of a pharmaceutical agent to suppress multiple resistance to cancer drugs, etc.| .

Preferably, a compound of the present invention or a combination agent of the present invention is administered orally (including sustained-release formulations), intravenously (including boluses, infusions, and clathrates), subcutaneously and intramuscularly (including boluses, infusions, and sustained-release formulations), transdermally, intratumorally, or proximally before or after carrying out the above-described treatment.

As a period for the administration of the compound of the present invention or the combined agent of the present invention before surgery, etc. may be, for example, the specified period in which 1-time administration is carried out within 30 minutes to 24 hours before surgical intervention, etc., or administration in 1-

C cycles for a period from about C months to b months before surgery, etc. In this way, surgical intervention, etc. can be carried out easily, since, for example, the cancerous tissue should be reduced due to the administration of the compound of the present invention or the combined agent of the present invention before surgery, etc.

As a period for the administration of the compound of the present invention or the combined agent of the present invention after surgery, etc., may be, for example, the period during which repeated administration is carried out for a time of about several weeks to 3 months after surgery, etc. . Thus, the effect of surgical intervention, etc. increases. due to the introduction of the compound of this invention or the combined means of this invention after surgical intervention, etc.

Examples

The present invention is explained in detail with the following reference to Supporting Examples, Examples,

Example Formulations and Experimental Examples, which should not be considered as limiting.

In the Auxiliary Examples and Examples, the purity of the compounds was determined under the following conditions

TOP. measuring device: ZNIMAO2Y system Sogrogayop I. S-10 Amr column: SARBEI. RAK C1800120 5-3 μm, 2.0 x 50 mm solvent: Solution A; 0.1 95 solution of trifluoroacetic acid in water,

Solution B; 0.1 95 solution of trifluoroacetic acid in acetonitrile gradient cycle: 0.00 minutes (Solution A/Solution B-90/10), 4.00 minutes (Solution A/Solution B-5/95), 5.50 minutes (Solution A/Solution B-5/95), 5.51 minutes (Solution A/Solution B-90/10), 8.00 minutes (Solution

A/Solution B-90/10) injection volume: 2 μl flow rate: 0.5 ml/min. method of determination: UV 220 nm

In the Auxiliary Examples and Examples, the compounds were purified using a preparative method

HPLC under the following conditions. 1) measuring device: cleaning system with high performance, Siizop Sotrapu Ips. column: UMO SotrBbiRger 005-A, 5-5 μm, 50 x 20 mm determination method: UV 220 nm solvent: Solution A; 0.1 95 solution of trifluoroacetic acid in water,

Solution B; 0.1 95 solution of trifluoroacetic acid in acetonitrile gradient cycle: typical example 0.00 minutes (Solution A/Solution B-98/2), 1.00 minutes (Solution

A/Solution B-98/2), 5.20 minutes (Solution A/Solution B-0/100), 6.40 minutes (Solution A/Solution B-0/100), 6.50 minutes (Solution A/ Solution B-98/2), 6.60 minutes (Solution A/Solution B-98/2), Extinguishing: 25 ml/min. or 0.00 minutes (Solution A/Solution B-90/10), 1.00 minutes (Solution A/Solution B-90/10), 4.00 minutes (Solution A/Solution B-10/95), 8 .50 minutes (Solution A/Solution B-10/95), 8.60 minutes (Solution A/Solution

B-90/10), 8.70 minutes (Solution A/Solution B-90/10) flow rate: 20 ml/min. 2) measuring device: cleaning system with high performance, biosop of Sotrap Ips. column: UMO SotrbiRger, RgoS18 K5, 5-5 μm, 20 x 50 mm (UMS) solvent: Solution A; 10 mM solution of ammonium carbonate in water,

Solution B; acetonitrile gradient cycle: 0.00 minutes (Solution A/Solution B-95/5), 2.00 minutes (Solution A/Solution B-95/5), 4.02 minutes (Solution A/Solution B-5/95 ), 6.40 minutes (Solution A/Solution B-5/95), 6.50 minutes (Solution

A/Solution B-95/5), 8.00 minutes (Solution A/Solution B-95/5) 3) measuring device: cleaning system with high productivity, Siizop Sotrapu Ips. column: UMO SotrbiRger, RgoS18 K5, 5-5 μm, 20 x 50 mm (UMS) solvent: Solution A; 0.1 95 solution of trifluoroacetic acid in water,

Solution B; 0.1 95 solution of trifluoroacetic acid in acetonitrile gradient cycle: 0.00 minutes (Solution A/Solution B-98/2), 1.00 minutes (Solution A/Solution B-98/2), 5.20 minutes (Solution A/Solution B-60/40), 5.40 minutes (Solution A/Solution B-5/95), 6.40 minutes (Solution

A/Solution B-5/95), 6.50 minutes (Solution A/Solution B-98/2), 6.60 minutes (Solution A/Solution B-98/2) injection volume: 500 μl , flow rate: 20 ml/min., detection method: UV 220 nm, 254 nm

In the Supporting Examples and Examples, the mass spectrum (MM) was determined under the following conditions. measuring device: Misgota55 rianogt II or UMaieg5 2MO method of ionization: chemical ionization at atmospheric pressure (ARSI) or ionization method by electron bombardment (electrospray ionization: E5I)

In the Auxiliary Examples and Examples, the HPLC-mass spectrum (LC-MS) was determined under the following conditions. 1) measuring device: Misgotav5 2MO, Adiepi Tesppoiodie5 НР1100 и 1200 РХ/)МСО column: SARSEI YII RAK С1800С1120, 5-3 μm, 1.5 x 35 mm solvent: SOLUTION A; 0.05 95 solution of trifluoroacetic acid in water,

SOLUTION B; 0.04 95 solution of trifluoroacetic acid in acetonitrile gradient cycle: 0.00 minutes (Solution A/Solution B-90/10), 2.00 minutes (Solution A/Solution B-5/95), 2.15 minutes (Solution A/Solution B-5/95), 2.76 minutes (Solution A/Solution B-90/10), 3.45 minutes (Solution

A/Solution B-90/10) injection volume: 2 μl flow rate: 0.5 ml/min. detection method: UV 220 nm ionization method: electron bombardment ionization method (electro-spray ionization: EBI) 2) measuring device: Umaiegv5, 4-SpP RH/MS system with MOX column: SARSEI ЯИ. RAK C18 Ob-120, 5-3 μm, 1.5 x 35 mm (Zpizeido Co., (a) solvent: Solution A; 5 mM solution of ammonium acetate in water,

Solution B; 5 mM solution of ammonium acetate in acetonitrile gradient cycle: gradient: 0.00 minutes (Solution A/Solution B-100/0), 2.00 minutes (Solution A/Solution

B-0/100), 3.00 minutes (Solution A/Solution B-0/100), 3.01 minutes (Solution A/Solution B-100/0), 3.30 minutes (Solution A/Solution B- 100/0) injection volume: 2 μl, flow rate: 0.5 ml/min., detection method: UV 220 nm ionization method: electrospray ionization (E5I) measurement mode: full scan (positive -- negative ions) range of measured mass values: t/2-:150-750

The IN-NMR spectrum was recorded using tetramethylsilane as an internal standard, using VKOKEV AMAMSE YuRH-300 (300 MHz), AM300 (300 MHz), AM400 (400 MHz) and MAKIAM

Megsigu-300 (300 MG), and all values of 5 are expressed in million units.

Etgu5 Oriiti7eg, Vioiade darap tsa were used as an apparatus for microwave reactions.

Unless otherwise noted, mixed solvent numerical values show the mixing ratios of each solvent by volume. Unless otherwise stated, 95 means wt. 95. Since room temperature (ambient temperature) in this description means a temperature from about 10 "C to about 35 "C, it was not specifically limited.

Other abbreviations used herein have the following meanings: c: singlet d: doublet t: triplet k: quartet m: multiplet sext: sextet w: broad y: splitting constant

Hz: Hertz

СОси»: deuterated chloroform

DMSO-dv: dimethylsulfoxide-dv

Source: deuterated methanol "H-NMR: proton nuclear magnetic resonance

LC/MS: spectrum of liquid chromatography-mass spectrometry

OME: M, M-dimethylformamide

DMSO: dimethyl sulfoxide

THF: tetrahydrofuran

MOR: water-soluble carbodiimide -- (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide) hydrochloride

NEW: 1-Hydroxybenzotriazole

Vos: tert-butoxycarbonyl

KSO": potassium carbonate

M: molar concentration

Auxiliary Example 1

Preparation of ethyl 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate

SOS"

M ()

N

To a solution of methyl anthranilate (121 g, 0.8 mol) and diethyl malonate (128 g, 0.8 mol) in ethanol (900 mL) was added a 2095 solution (274 g) of sodium ethoxide in ethanol, and the mixture was stirred at room temperature for 30 minutes . Ethanol was evaporated, and the mixture was stirred at 140°C for 12 hours. After cooling, the resulting solid was washed with diethyl ether and dissolved in water. Insoluble materials were filtered off, the filtrate was acidified with 5M hydrochloric acid, and the precipitated solid was collected by filtration. The resulting solid was washed water and dried under reduced pressure, obtaining the title compound (161 g, 86 95) as a pale yellow powder. 7.1 Gu), 4.34 (2H, k, 9U-7.1 Gu), 7.19-7.29 (2H, m), 7.63 (IN, td, 9U-7.8, 1 ,2 Hz), 7.94 (1H, d, U-8.1 Hz), 11.51 (1H, w s), 13.40 (IN, w s).

Auxiliary Example 2

Production of ethyl 2,4-dichloroquinoline-3-carboxylate

SI o o

M SI

A mixture of the compound of Auxiliary Example 1 (75 g, 0.32 mol) and phosphorus oxychloride (200 ml) was stirred at 110 "C for 6 hours. After cooling, the reaction mixture was concentrated under reduced pressure, the residue was dissolved in a small amount of ethyl acetate, and the mixture was poured into ice water. The resulting mixture was extracted with ethyl acetate, and the extract was washed successively with 1M aqueous sodium hydroxide solution, water, and saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography on amino silica gel (eluate; ethyl acetate/hexane-1/5 ), obtaining the title compound (68 g, 79 90) in the form of a white solid. .54 (2H, k, 9U-7.2 Hz), 7.71 (IN, t, 9-7.5 Gu), 7.85 (IN, t, U-7.5 Hz), 8.06 (1H, d, 9U-8.2 Hz), 8.24 (1H, d, U-8.2 Gu).

Auxiliary Example Z

Production of ethyl 4-chloro-2-oxo-1,2-dihydroquinoline-3-carboxylate

SI

SSO"

M F)

N

A mixture of the compound of Auxiliary Example 2 (68.0 g, 0.25 mol) and sodium acetate (21.7 g, 0.26 mol) in acetic acid (200 ml) was stirred at 120 "C for 20 hours. After cooling, the reaction mixture was added to water, and the precipitated solid was collected by filtration. The resulting solid was washed with water and dried under reduced pressure to give the title compound (58.8 g, 94 95) as a white solid. "H-NMR ( 300 MHz, SOSIZz) 5: 1.46 (ZH, t, 9U-7.2 Hz), 4.53 (2H, k, 9U-7.2 Hz), 7.34 (1H, t, U-7 .8 Hz), 7.43 (IN, d, U-8.1 Hu), 7.63 (1H, t, 9U-7.8 Hu), 8.00 (1H, d, 9U-8.1 Hz), 12.41 (IN, w s).

Auxiliary Example 4

Production of ethyl 4-chloro-2-oxo-1-(2-oxo-2-phenylethyl)-1,2-dihydroquinoline-3-carboxylate

SI

SOS" m so ri

To a solution of the compound of Auxiliary Example C (10.0 g, 39.7 mmol) in DMF (160 mL) was added sodium hydride (60 95 in oil, 1.7 g, 41.7 mmol) while cooling on ice. and the mixture was stirred for 15 minutes. Phenacyl bromide (8.7 g, 43.7 mmol) was added to the resulting mixture while cooling on ice, and the mixture was stirred for 1 hour. The reaction mixture was added to water (1.5 L) and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluate; ethyl acetate/hexane-1/2-1/1) to give the title compound (10.5 g, 71 95) as a pale yellow solid. "H-NMR (300 MHz, SOSI") 6: 1.42 (ZH, t, 9-7.2 Hz), 4.47 (2H, k, 9-7.2 Hu), 5.80 (2H , c), 7.02 (1H, d, 9-8.1 Hu), 7.34 (1H, t, U-7.8 Hu), 7.53-7.60 (ZH, m), 7 .65-7.70 (1Н, m), 8.06-8.13 (ЗН, m).

Auxiliary Example 5

Preparation of 3-hydroxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno|3,2-s|quinoline-2-carboxylate

SO shchi same he

Mm'so ri 965 solution (17.2 g, 50.5 mmol) of sodium ethoxide in ethanol was diluted with ethanol (50 ml), ethyl thioglycolate (6.1 g, 50.5 mmol) was added to the resulting solution, and the mixture was stirred at room temperature within 5 minutes. The compound of Auxiliary Example 4 (9.3 g, 25.3 mmol) was added to the mixture and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with ice water (50 ml), 2M hydrochloric acid (30 ml) was added and the mixture was stirred for 30 minutes. The resulting solid was collected by filtration, washed with water and diethyl ether, and dried under reduced pressure to give the title compound (10.0 g, 96 95) as a white powder. "H-NMR (300 MHz, DMSO-av) 6: 1.32 (ZH, t, 9-7.0 Hu), 4.25-4.35 (2H, m), 6.01 (2H, s ), 7.40 (1H, t,

U7.2 Gu), 7.55-7.67 (4H, m), 7.77 (1H, t, U-7.5 Hz), 8.00-8.07 (1H, m), 8, 07-8.19 (2H, m), 10.40-10.65 (1H, shsh).

Auxiliary Example 6

Preparation of 3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno|3,2-c)yquinoline-2-carboxylate

SOEI is OMe

M .6) ri

A mixture of the compound of Auxiliary Example 5 (7.0 g, 17.1 mmol) and OVI (4.3 g, 18.3 mmol) in DMF (150 mL) was stirred at room temperature for 10 minutes, and iodomethane (4.0 g, 28.0 mmol). The mixture was stirred at room temperature for 4 hours and concentrated under reduced pressure. The residue was diluted with water and extracted twice with a mixture of ethyl acetate-

THF. The extracts were combined, washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was washed with a solvent mixture of ethyl acetate-diethyl ether and dried under reduced pressure, obtaining the title compound (5.7 g, 79 Fo) as a pale green powder. "H-NMR (300 MHz, DMSO-α) 6: 1.34 (ZH, t, U-7.1 Gu), 3.95 (ZH, s), 4.34 (2H, k, 9-71 Hz), 5.98 (2H, s), 7.37 (IN, t, U-7.5 Gu), 7.49 (1H, d, U-8.7 Hz), 7.57-7, 67 (ZN, m), 7.76 (1TN, t, U-7.5 Gu), 8.06 (1Н, d, 9U-7.8

Hz), 8.16-8.19 (2H, m).

Auxiliary Example 7

Preparation of 3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno|3,2-c)quinoline-2-carboxylic acid

MO ri

A mixture of a solution of the compound of Auxiliary Example b (5.7 g, 13.5 mmol) and a 2M aqueous solution of sodium hydroxide (60 ml) in THF (200 ml)-ethanol (100 ml) was stirred at room temperature for 18 hours. The reaction mixture was neutralized with 2M hydrochloric acid (60 mL) and the precipitated solid was collected by filtration. The resulting solid was washed successively with water and diethyl ether and dried under reduced pressure to give the title compound (4.2 g, 79 95) as a pale pink powder. "H-NMR (300 MHz, DMSO-α) 6: 3.93 (ZH, s), 5.98 (2H, s), 7.35 (1H, t, U-7.8 Hu), 7, 48 (1H, d, 9U-8.7 Gu), 7.56-7.67 (ZH, m), 7.77 (IN, t, 9U-7.2 Gu), 8.04 (1H, dd , 9U-8.1, 1.2 Hz), 8.16-8.19 (2Н, m).

Auxiliary Example 8

Preparation of 3-ethoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoi|3,2-c)quinoline-2-carboxylate so z - Fi

Mo; ri

By a procedure similar to that given in Auxiliary Example 6, the title compound (461 mg, 87 95) was obtained as a white powder from the compound (500 mg, 1.22 mmol)

Auxiliary Example 5, OVA (280 mg, 1.84 mmol) and iodethane (302 mg, 1.84 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.34 (6H, t, 9U-7.0 Hz), 4.21 (2H, k, 9U-7.0 Hz), 4.34 ( 2H, k, 9U-7.0 Hu), 5.98 (2H, s), 7.35 (1H, t, U-7.5 Hu), 7.49 (1H, d, U-8.4 Gu), 7.57-7.67 (ZN, m), 7.76 (1H, t, 9U-7.2 Gu), 8.06 (IN, dd, U-7.8, 1.2 Hz ), 8.16-8.19 (2H, m).

Auxiliary Example 9

Preparation of 3-ethoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoic|3,2-c|quinoline-2-carboxylic acid

M 6)

H

By a procedure similar to that given in Auxiliary Example 7, the title compound (392 mg, 95 95) was obtained as a pale pink powder from the compound (440 mg, 1.01 mmol)

Auxiliary Example 8. "H-NMR (300 MHz, DMSO-α) 6: 1.33 (ЗН, т, 9-7.0 Hz), 4.20 (2Н, к, 9У-7.0 Hz), 6.00 (2H, s), 7.35 (1H, t, 9-7.5 Hz), 7.47 (IN, d, U-8.4 Hz), 7.56-7.67 (ЗН , m), 7.77 (1H, t, 9U-7.5 Hz), 8.04 (1H, dd, 9U-7.8, 1.2 Gu), 8.16-8.19 (2H, m).

Auxiliary Example 10

Production of ethyl 4-chloro-1-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-3-carboxylate

SI

SS

Mo; month -

By a procedure similar to that given in Auxiliary Example 4, the title compound (10.8 g, 79 95) was obtained as a white powder from the compound (10.0 g, 39.8 mmol) of Auxiliary

Example C and 4-methoxybenzyl chloride (7.48 ml, 47.8 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.34 (ZH, t, U-7.1 Hu), 3.70 (ZH, s), 4.40 (2H, k, 9-71 Hz), 5.48 (2H, s), 6.89 (2H, d, 9-8.7 Gu), 7.19 (2H, d, 9U-8.7 Hz), 7.42 (1H, t, U-7.8 Hz), 7.61 (1H, d, 9U-8.7 Hz), 7.69-7.75 (1H, m), 8.04 (1H, dd, U-7 ,8,1,2 Gu).

Auxiliary Example 11

Preparation of 3-hydroxy-5-(4-methoxybenzyl)-4-oxo-4,5-dihydrothieno|Ж3,2-с|quinoline-2-carboxylate

CO

TK

HE still has heh, mmeo.

By a procedure similar to that given in Auxiliary Example 5, the title compound (10.4 g, 88 95) was obtained as a white powder from the compound (10.6 g, 31.0 mmol) of Auxiliary

Example 10. "H-NMR (300 MHz, DMSO-α) 6: 1.32 (ZH, t, U-7.0 Hz), 3.70 (ZH, s), 4.32 (2H, k, 9-7.0 Hz), 5.53 (2H, s), 6.87 (2H, d, 9U-8.9 Hz), 7.23 (2H, d, 9U-8.9 Hz), 7 ,34-7.39 (1H, m), 7.58-7.66 (2H, m), 8.00-8.03 (1H, m), 10.77 (IN, s).

Auxiliary Example 12

Preparation of 3-methoxy-5-(4-methoxybenzyl)-4-oxo-4,5-dihydrothieno|3,2-c|quinoline-2-carboxylate

SOY same p OMe

Mo mmeo Fr

By a procedure similar to that given in Auxiliary Example 6, the title compound (5.2 g, 64 95) was obtained as a white powder from the compound (7.5 g, 19.8 mmol) of Auxiliary

Example 11. "H-NMR (300 MHz, DMSO-α) 6: 1.34 (ZH, t, U-7.1 Hu), 3.70 (ZH, s), 4.01 (ZH, s) , 4.34 (2H, k, 9-71 Gu), 5.50 (2H, s), 6.87 (2H, d, 9-8.7 Hz), 7.20 (2H, d, 9U- 8.7 Hz), 7.27-7.32 (1H, m), 7.48-7.60 (2H, m), 8.01 (1H, dd, U-7.7, 1.4 Gu ).

Auxiliary Example 13

Preparation of 3-methoxy-5-(4-methoxybenzyl)-4-oxo-4,5-dihydrothieno|3,2-s|quinoline-2-carboxylic acid

СО,Н счи с ОМе

M o)

Me.

By a procedure similar to that given in Auxiliary Example 7, the title compound (4.75 g, 98 95) was obtained as a white powder from the compound (5.0 g, 12.3 mmol) of Auxiliary

Example 12. "H-NMR (300 MHz, DMSO-α) 6: 3.70 (ZH, s), 3.93 (ZH, s), 5.51 (2H, s), 6.87 (2H, d, 9U-8.7 Hz), 7.20 (2H, d, 9U-8.7 Hz), 7.27-7.32 (1H, m), 7.48-7.59 (2H, m ), 7.99 (1H, dd, U-7.8, 1.2 Gu), 13.40 (1H, s).

Auxiliary Example 14

Preparation of 1-(pyridin-2-ylmethyl)-2H-3,1-benzooxazin-2,A(1H)-dione (o) sorinche t

AM

2-(Chloromethyl)pyridine hydrochloride (28.1 g, 0.171 mol) and sodium hydride (66 95 in oil, 12.5 g, 0, 34 mol) when cooled on ice. The resulting mixture was stirred at room temperature for 42 hours. Water (750 ml) was added to the reaction mixture and the mixture was cooled on ice. The resulting solid was collected by filtration and recrystallized from acetone-isopropyl ether to give the title compound (13.4 g, 34 95). "H-NMR (300 MHz, DMSO -av) 6:5.36 (2H, s), 7.24-7.34 (ZH, m), 7.49 (1H, d, 9U-8.1 Hu ), 7.73 (1H, ddd, 9-8.6, 7.2, 1.5 Hz), 7.77 (1H, td, 9U-7.7, 1.6 Gu), 8.03 ( 1H, dd, 9U-7.8, 1.8 Gu), 8.50 (1H, ddd, U-4.9, 1.7, 1.0

Gu).

Auxiliary Example 15

Preparation of ethyl 4-hydroxy-2-oxo-1-(pyridin-2-ylmethyl)-1,2-dihydroquinoline-3-carboxylate one zy BOB shk

M o -kh

M

To a solution of diethylmalonate (15.6 g, 97.4 mmol) in DMF (90 mL) was added sodium hydride (66 95 in oil, 2.60 g, 72 mmol) while cooling on ice, and the mixture was stirred at the same temperature for 10 minutes The auxiliary compound was added in small portions to the resulting mixture

Example 14 (16.5 g, 64.9 mmol) and the mixture was stirred at 120 "C for 6 hours. The reaction mixture was concentrated under reduced pressure, ice water was added to the residue, and the mixture was washed with diethyl ether. The aqueous layer was slightly basified with 5M hydrochloric acid ( 8 mL) while cooling on ice.The precipitated crystals were collected by filtration, washed with water, and recrystallized from ethyl acetate-diisopropyl ether to give the title compound

(12.8 g, 60 Ob). "H-NMR (300 MHz, SOSI") 6: 1.50 (ZH, t, 9U-7.1 Hu), 4.53 (2H, k, 9U-7.1 Hu), 5.61 (2H , w s), 7.12-7.18 (2H, m), 7.18-7.25 (1H, m), 7.36 (1H, d, 9U-8.7 Hz), 7.51 -7.59 (2H, m), 8.18 (1H, dd, uU-8.3, 1.7 Gu), 8.56 (1H, dd, 9-5.3, 2.0 Hz), 14.53 (1H, s).

Auxiliary Example 16

Preparation of ethyl 4-chloro-2-oxo-1-(pyridin-2-ylmethyl)-1,2-dihydroquinoline-3-carboxylate

SI

CO

Su ry

M F)

She - M

To a mixture of the compound of Auxiliary Example 15 (16.1 g, 49.6 mmol) and toluene (50 ml) was added phosphorus oxychloride (12 ml, 0.13 mol) and the mixture was stirred at 110 C for 1 hour.

The reaction mixture was allowed to cool and the solvent was removed by decantation. Water was added to the residue and the mixture was washed with diethyl ether. The aqueous layer was neutralized with sodium carbonate and extracted twice with chloroform. The combined organic layer was washed with water and saturated saline, dried over sodium sulfate, filtered and concentrated under reduced pressure.

The residue was purified by column chromatography on silica gel (eluate; ethyl acetate/hexane-1/1-3/1) and crystallized from ethyl acetate-hexane to give the title compound (2.54 g, 15 Urv). "H-NMR (300 MHz, SOSIz) 5: 1.44 (ZH, t, 9U-7.2 Hz), 4.50 (2H, k, 9U-7.2 Hz), 5.64 (2H, w s), 7.15-7.26 (2H, m), 7.91 (1H, ddd, U-8.2, 5.9, 2.3 Hz), 7.52-7.63 (ЗН , m), 8.06 (1H, dt, uU-7.8, 0.8 Hz), 8.56 (1H, ddd, 3-4.7, 1.9, 0.8 Gu).

Auxiliary Example 17

Preparation of 3-hydroxy-4-oxo-5-(pyridin-2-ylmethyl)-4,5-dihydrothieno|3,2-c|quinoline-2-carboxylate

SO"!

R Wed On

M o p -M 95 solution (4.51 g, 13 mmol) of sodium ethoxide in ethanol was diluted with ethanol (15 ml) and ethyl thioglycolate (1.74 ml, 15.9 mmol) was added to the resulting solution. The mixture was stirred at room temperature for 10 minutes. The compound of Auxiliary Example 16 (2.27 g, 6.62 mmol) was added to the mixture and the mixture was stirred at room temperature for 5.5 hours. The reaction mixture was neutralized with ice water and 2M hydrochloric acid (3.2 mL) while cooling on ice, and extracted twice with chloroform. The combined organic layer was washed with water and saturated saline, dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained solid was washed with ethanol to give the title compound (2.50 g, 99 Fo). "H-NMR (300 MHz, SOSI") 6: 1.43 (ZH, t, 9U-7.1 Hu), 4.43 (2H, k, U-7.1 Hu), 5.69 (2H , w c), 7.16-7.24 (2H, m), 7.25-7.32 (1H, m), 7.49 (1H, ddd, 9U-8.6, 7.1, 1 .5 Hu), 7.57 (1H, d, 9-81 Hu), 7.60 (1H, td, 9-7.7, 1.8

Hu), 7.82 (1H, dd, 9U-8.1, 1.5 Hz), 8.57 (1H, ddd, U-4.9, 1.6, 0.8 Gy), 10.68 (1H, p).

Auxiliary Example 18

Preparation of 3-methoxy-4-oxo-5-(pyridin-2-ylmethyl)-4,5-dihydrothienoic acid 3,2-squinoline-2-carboxylate

SO sh rik Z

M o

Another M

To a suspension of the compound of Auxiliary Example 17 (2.26 g, 5.94 mmol) in DMF (20 mL) was added OVO (1.06 mL, 7.09 mmol) and to the resulting solution was added iodomethane (0.74 mL, 12 mmol) ). The resulting mixture was stirred at room temperature for 14 hours, water was added and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with water, 0.5M sodium hydroxide solution and water, dried by passing through basic silica gel (eluted with ethyl acetate) and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-diisopropyl ether to give the title compound (1.16 g, 50 95). "H-NMR (300 MHz, SOSIzv) 6: 1.43 (ZH, t, 9U-7.1 Hz), 4.17 (ZH, s), 4.41 (2H, k, 9-71 Gu) , 5.70 (2H, w s), 7.14-7.26 (ZH, m), 7.45 (1H, ddd, 9U-8.6, 7.0, 1.6 Hz), 7, 51 (1IN, dd, 9U-8.6, 0.8 Gu), 7.57 (1Н, td, 9U9-7.7, 1.8

Hz), 7.83 (1H, ddd, 927.7, 1.5, 0.3 Hz), 8.57 (1H, ddd, 4-5.0, 2.0, 0.9 Hz).

Auxiliary Example 19

Preparation of 3-methoxy-4-oxo-5-(pyridin-2-ylmethyl)-4,5-dihydrothieno|III3,2-c|quinoline-2-carboxylic acid

SLEEP

5- goh with OoMe

M o

And m

To a suspension of the compound of Auxiliary Example 18 (1.21 g, 3.07 mmol) in THF (10 ml) and ethanol (10 ml) was added a 5M aqueous solution of sodium hydroxide (1.2 ml, 6.0 mmol). The resulting mixture was stirred at room temperature for 45 minutes, ethanol (5 ml) was added and the mixture was stirred for the next 135 minutes. The reaction mixture was cooled on ice, neutralized with 1M hydrochloric acid (6.0 mL), and chloroform and water were added. The organic layer was separated and the aqueous layer was extracted twice with chloroform. The combined organic layer was washed with water and saturated saline, dried over sodium sulfate, filtered and concentrated under reduced pressure.

The residue was recrystallized from chloroform-diisopropyl ether to give the title compound (1.11 g, 99 Urv). "H-NMR (300 MHz, DMSO-α) 6: 3.96 (ZH, s), 5.65 (2H, s), 7.23-7.33 (ZH, m), 7.43 (1H , d, 9U-8.7 Hz), 7.54 (1H, ddd, 9U-8.6, 7.3, 1.4 Hz), 7.73 (1H, td, 9U-7.7, 1 .9 Hz), 7.97-8.02 (1H, m), 8.45-8.48 (1H, m), 13.38 (IN, w s).

Auxiliary Example 20

Preparation of 3-(2-ethoxyethoxy)-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno|3,2-c|quinoline-2-carboxylate

SozE! ste s r . m o OEI 05 and yo

To a suspension of the compound of Auxiliary Example 5 (1.35 g, 3.31 mmol) in DMF (20 mL) was added OVIU (1.48 mL, 9.90 mmol) and 2-bromoethyl ether (1.12 mL, 9.93 mmol), and the mixture was stirred at 60 "C for 30 hours. Chloroform and water were added to the reaction mixture, the organic layer was separated and the aqueous layer was extracted with chloroform. The combined organic layer was washed with 0.5M sodium hydroxide solution and water and concentrated under reduced pressure The residue was purified by column chromatography on silica gel (eluate: ethyl acetate/hexane-1/3-2/3) and recrystallized from dichloromethane-diisopropyl ether, obtaining the title compound (1.36 g, 86 Vol). "H- NMR (300 MHz, SOSI»z) 5: 1.17 (ZN, t, 9U-7.1 Hu), 1.43 (ZN, t, 9-71 Hu), 3.56 (2H, k, 9 -71 Gu), 3.89 (2H, dd, 9-5.5, 4.6 Hz), 4.40 (2H, k, 9-71 Hz), 4.45 (2H, dd, 9U-5 .5, 4.6 Hz), 5.85 (2H, s), 6.97 (1H, d, 9U-8.1

Gu, 7.21-7.28 (1H, m), 7.45 (1H, ddd, 9U-8.7, 7.2, 1.4 Hz), 7.51-7.58 (2H, m ), 7.63-7.69 (1H, m), 7.86 (1H, dd, 9-7.8, 1.5 Hu), 8.07-8.12 (2H, m).

Auxiliary Example 21

Preparation of 3-(2-ethoxyethoxy)-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno|3,2-c|quinoline-2-carboxylic acid

SLEEP

R co

M' OE! rya

To a suspension of the compound of Auxiliary Example 20 (1.20 g, 2.50 mmol) in THF (16 ml) and ethanol (16 ml) was added a 5M aqueous solution of sodium hydroxide (1.0 ml, 5.0 mmol). The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was acidified with 1M hydrochloric acid and water was added. The precipitated crystals were collected by filtration and washed with water to give the title compound (1.09 g, 97 U). "H-NMR (300 MHz, DMSO-α) 6: 1.01 (ZH, t, U-6.9 Hz), 3.40 (2H, k, 9U-6.9 Hz), 3.71 ( 2H, t, 9-5.0 Hz), 4.30 (2H, t, U-5.0 Gu), 5.97 (2H, s), 7.33 (1H, t, 9U-7.7 Hu), 7.46 (1H, d, U-8.7 Hu), 7.54-7.66 (ZH, m), 7.76 (IN, t, U-7.2 Hu), 8, 02 (1H, d, U-7.8 Gu), 8.16 (2H, d, 9-7.5 Gu), 13.27 (IN, w s).

Auxiliary Example 22

Preparation of 3-hydroxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrofuro|3,2-c)quinoline-2-carboxylate

SO and -

M (in, x

By a procedure similar to that given in Auxiliary Example 5, the title compound (1.10 g, 69 95) was obtained as a white powder from the compound of Auxiliary Example 4 (1.50 g, 4.06 mmol), 20 95 of a solution (2.76 g, 8.11 mmol) of sodium ethoxide in ethanol and ethyl glycolate (1.01 g, 9.73 mmol). "H-NMR (300 MHz, DMSO-av) 5: 1.34 (ZH, t, 9U-7.1 Hz), 4.35 (2H, k, 9-7.1 Hz), 5.96 ( 2H, c), 7.39 (1H, t,

У7.7 Gu), 7.51 (IN, d, У-8.4 Hz), 7.60-7.67 (ЗН, m), 7.74-7.79 (1Н, m), 8, 05 (1H, dd, 9-7.7, 1.4 Hz), 8.15-8.18 (2H, m), 9.80-11.10 (1H, w).

Auxiliary Example 23

Preparation of 3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrofuro|3,2-c)quinoline-2-carboxylate

CO

8

SSS Sh what

MOTO I

She

By a procedure similar to that given in Auxiliary Example 6, the title compound (250 mg, 23 95) was obtained as a white powder from the compound of Auxiliary Example 22 (1.05 g, 2.688 mmol), OVIi (612 mg, 4 .02 mmol) and iodomethane (250 μl, 4.02 mmol). "H-NMR (300 MHz, DMSO-av) 6: 1.35 (ZH, t, U-7.1 Hz), 4.14 (ZH, s), 4.37 (2H, k, 9-71 Hz), 5.99 (2H, s), 7.39-7.45 (1H, m), 7.55 (IN, d, U-8.7 Hz), 7.62-7.68 (ЗН , m), 7.74-7.80 (1H, m), 8.09 (1H, dd, 9U-7.8, 1.5 Gu), 8.16-8.18 (2H, m).

Auxiliary Example 24

Preparation of 3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrofuroyl3,2-c)quinoline-2-carboxylic acid

J

With more OoMe ryn and Mm'To o. and railway

By a procedure similar to that given in Auxiliary Example 7, the title compound (160 mg, 72 95) was obtained as a white powder from the compound of Auxiliary Example 23 (240 mg, 0.592 mmol), 8M aqueous sodium hydroxide solution (1, 0 ml) and ethanol (14 ml). "H-NMR (300 MHz, DMSO- av) 6: 4.12 (ZH, s), 5.99 (2H, s), 7.42 (1H, t, U-7.6 Hu), 7, 54 (1H, d, 9U-7.8 Hz), 7.62-7.67 (ZH, m), 7.77 (1H, t, U-7.8 Hz), 8.07 (1H, dd , 9U-7.6, 1.5 Hz), 8.16-8.18 (2Н, m), 12.60-1410 (1Н, шш).

Auxiliary Example 25

Production of soybean ethyl 4-(2-ethoxy-2-oxoethyl)(methyl)amino|-2-oxo-1-(2-oxo-2-phenylethyl)-1,2-dihydroquinoline-3-carboxylate

Me. Wed on

M o) in

A mixture of the compound of Auxiliary Example 4 (24.1 g, 65.2 mmol), sarcosine ethyl ester hydrochloride (12.0 g, 78.2 mmol), triethylamine (18.1 ml, 130 mmol) and ethanol (200 ml) was stirred at 85 "C for 15 hours, then sarcosine ethyl ester hydrochloride (3.00 g, 19.6 mmol) and triethylamine (18.1 ml, 130 mmol) were added, and the mixture was stirred at 85 "C for 7 hours. After cooling, water was added to the reaction mixture and the precipitated solid was collected by filtration. The resulting solid was washed with water and dried under reduced pressure to give the title compound (24.6 g, 84 95) as a white powder. "H-NMR (300 MHz, DMSO-α) 6: 1.21-1.31 (6H, m), 2.93 (ZH, s), 3.95 (2H, s), 4.15-4 .31 (4H, m), 5.87 (2H, s), 7.31 (IN, t, U-7.8 Hz), 7.40 (1H, d, 9U-8.4 Hz), 7 ,55-7.65 (ZH, m), 7.72-7.78 (1H, m), 8.05 (1H, dd, 9-7.8, 1.5 Gu), 8.12-8 ,15 (2H, m).

Auxiliary Example 26

Preparation of 3-hydroxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo|3,2-c)quinoline-2-carboxylate

Me so

M. H

Mr. Mr

Sho) (6) -e

Sho and

A mixture of the compound of Auxiliary Example 25 (1.25 g, 2.77 mmol), 20 95 solution (1.23 g, 3.33 mmol) of sodium ethoxide in ethanol and ethanol (25 ml) was stirred at 55 "C for 15 hours. The reaction mixture was diluted with water, 1M hydrochloric acid (5 mL) was added, and the mixture was stirred for 30 min. The resulting solid was collected by filtration, washed with water, ethanol, and ethyl acetate, and recrystallized from dimethylformamide-ethanol to give the title compound (760 mg 68 95) in the form of a white powder. "H-NMR (300 MHz, DMSO-av) 5: 1.33 (ZH, t, U-7.2 Gu), 4.30-4.38 (5Н, m) , 5.93 (2H, s), 7.30-7.40 (2H, m), 7.48-7.53 (1H, m), 7.61-7.66 (2H, m), 7 .73-7.79 (1H, m), 8.15-8.18 (2H, m), 8.34-8.37 (1H, m), 9.00 (IN, s).

Auxiliary Example 27

Preparation of 3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo|3,2-c)quinoline-2-carboxylate

Me so. "M x a OoMe

M (F) 7

By a procedure similar to that given in Auxiliary Example 6, the title compound (420 mg, 55 95) was obtained as a white powder from the compound of Auxiliary Example 26 (740 mg, 1.83 mmol), OVIi (410 μl, 2 .74 mmol) and iodomethane (171 μl, 2.74 mmol). "H-NMR (300 MHz, DMSO-av) 6: 1.35 (ZH, t, 9U-7.1 Hz), 3.89 (ZH, s), 4.29-4.37 (5H, m ), 5.96 (2H, s), 7.30-7.40 (2H, m), 7.48-7.53 (1H, m), 7.61-7.66 (2H, m), 7.73-7.78 (1H, m), 8.15-8.18 (2H, m), 8.38 (1H, dd, 9-8.3, 1.4 Hu).

Auxiliary Example 28

Preparation of 3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo|3,2-c)quinoline-2-carboxylic acid

Me So "M H

Fo OoMe -y tmMto o

SHCI p

By a procedure similar to that given in Auxiliary Example 7, the title compound (345 mg, 91 95) was obtained as a white powder from the compound of Auxiliary Example 27 (405 mg, 0.968 mmol), 8M aqueous sodium hydroxide solution (1, 5 ml) and ethanol (15 ml). "H-NMR (300 MHz, DMSO-α) 6: 3.88 (ZH, s), 4.31 (ZH, s), 5.95 (2H, s), 7.29-7.39 (2H , m), 7.46-7.52 (IN, m), 7.61-7.66 (2Н, m), 7.73-7.78 (1Н, m), 8.16-8.18 (2H, m), 8.38 (1H, dd, U-8.3, 1.1 Hz), 12.92 (1H, s).

Auxiliary Example 29

Preparation of /3-ethoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo|3,2-c)quinoline-2-carboxylate

Me so sh-i x s sg oyi ry

M o o

What is it?

By a procedure similar to that given in Supplementary Example 6, the title compound (2.10 g, quant.) was obtained as a white powder from the compound (1.90 g, 4.70 mmol)

Auxiliary Example 26, OVI (1.05 ml, 7.05 mmol) and iodate (564 μl, 7.05 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.27-1.37 (6H, m), 4.16 (2H, k, U-6.9 Hz), 4.29-4.36 (5H, m), 5.95 (2H, s), 7.27-7.39 (2H, m), 7.50 (1H, t, U-8.0 Gu), 7.63 (2H, t, U-7.3 Hu), 7.76 (1H, t, U-7.4 Hu), 8.17 (2H, d, 9-73

Hz), 8.38 (TN, d, 9U-8.1 Hz).

Auxiliary Example 30

Preparation of /3-ethoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo|3,2-c)quinoline-2-carboxylic acid

Me Son i t og

M o) r:

By a procedure similar to that given in Auxiliary Example 7, the title compound (1.62 g, 89 95) was obtained as a white powder from the compound of Auxiliary Example 29 (1.95 g, 4.51 mmol), 8M aq. sodium hydroxide solution (2.0 ml) and ethanol (14 ml). "H-NMR (300 MHz, DMSO-α) 5: 1.27 (ZH, t, 9-7.0 Hz), 4.16 (2H, k, 9-7.0 Hu), 4.31 ( ZH, s), 5.95 (2H, s), 7.27-7.39 (2H, m), 7.49 (1H, t, U-7.4 Hz), 7.63 (2H, t , 9U-7.4 Hz), 7.76 (1TN, t, U-7.4 Gu), 8.15-8.18 (2Н, m), 8.38 (1TN, d, 9U-7, 2 Hz), 12.83 (1H, s).

Auxiliary Example 31

Preparation of ethyl 4-chloro-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate

SI

Me M (o)

N

A mixture of ethyl 4-hydroxy-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate (3.00 g, 15.2 mmol), phosphorus oxychloride (7.75 mL), n-butyltriethylammonium chloride (13 .8 g, 60.8 mmol) and acetonitrile (60 ml) were stirred at 40 "C for 30 minutes and under reflux for minutes. After cooling, the reaction mixture was concentrated under reduced pressure, water was added to the residue and the mixture extracted with ethyl acetate. The extract was washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with ethyl acetate-hexane solvent mixture and dried under reduced pressure to give the title compound (1.45 g, 44 95) as a white powder . "H-NMR (300 MHz, DMSO-α) 5: 1.26 (ЗН, t, 9-7.0 Hz), 2.20 (ЗН, s), 4.25 (2Н, k, 9- 7.0 Hz), 6.26 (1H, s), 12.29 (1H, s).

Auxiliary Example 32

Production of ethyl 4-chloro-6-methyl-2-oxo-1-(2-oxo-2-phenylethyl)-1,2-dihydropyridine-3-carboxylate

SI in the eyes

Me M'O rya

A mixture of the compound of Auxiliary Example 31 (9.00 g, 41.7 mmol), potassium carbonate (17.3 g, 125 mmol), phenacyl bromide (16.6 g, 83.5 mmol), and DMF (100 mL) was stirred at room temperature temperature for 15 hours. The reaction mixture was poured into water (100 mL) and the mixture was extracted with ethyl acetate.

The extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on amino silica gel (eluate; ethyl acetate/hexane-1/9-7/3) to give the title compound (3.18 g, 23 95) as a white powder. "H-NMR (300 MHz, DMSO-av) 6: 1.25 (ZH, t, U-7.0 Hu), 2.30 (ZH, s), 4.25 (2H, k, 9U-7 ,0 Hz), 5.63 (2H, s), 6.54 (1H, d, U-0.6 Hz), 7.61 (2H, t, 9-7.5 Hz), 7.72- 7.78 (IN, m), 8.07-8.10 (2Н, m).

Auxiliary Example 33

Preparation of 3-hydroxy-1,6-dimethyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo|3,2- cIpyridine-2-carboxylate

Me coolant

M

- HE

Me MO rya

A mixture of the compound of Auxiliary Example 32 (2.00 g, 5.99 mmol), sarcosine ethyl ester hydrochloride (1.84 g, 12.0 mmol), triethylamine (4.98 ml, 36.0 mmol) and ethanol (20 ml ) was stirred at 80 °C for 15 hours, a 2095 solution (3.5 ml) of sodium ethoxide in ethanol was added, and the mixture was stirred at 100 °C for 24 hours. After cooling, the reaction mixture was diluted with water (50 ml), EM hydrochloric acid was added, adjusting to pH 3-4 and the mixture was stirred for 30 min.The resulting solid was collected by filtration and washed with water and ethyl acetate/THF to afford the title compound (1.50 g, 68 95) as a white powder. "H-NMR (300 MHz, DMSO-av) 6: 1.31 (3 Н, t, 9-71 Hz), 2.26 (З3Н, s), 3.77 (ЗН, s), 4.30 (2 H, k, U-7.0

Hz), 5.57 (2 N, s), 6.52 (1 N, s), 7.54-7.67 (2 N, m), 7.69-7.79 (1 N, m) , 8.03-8.18 (2 N, m), 8.90 (1 N, s).

Auxiliary Example 34

Preparation of 3-methoxy-1,6-dimethyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo|3,2- cIpyridine-2-carboxylate

Me SO

M

- OoMe

Me MO rya

By a procedure similar to that given in Auxiliary Example 6, the title compound (390 mg, 26 95) was obtained as a white powder from the compound of Auxiliary Example 33 (1.45 g, 3.94 mmol), OVIi (882 μl , 5.90 mmol) and iodomethane (367 μl, 5.90 mmol). "H-NMR (300 MHz, DMSO-av) 6: 1.30 (With H, t, 9-7.1 Hu), 2.28 (With H, s), 3.81 (With H, s) , 3.86 (Z H, c), 4.27 (2

N, k, 9-7.0 Hz), 5.60 (2 N, s), 6.59 (1 N, s), 7.54-7.66 (2 N, m), 7.69- 7.79 (1 N, m), 8.05-8.16 (2 N, m).

Auxiliary Example 35

Preparation of 3-methoxy-1,6-dimethyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo|3,2- c|Ipyridine-2-carboxylic acid

Me SON

M with OMe

Me MO re

By a procedure similar to that given in Auxiliary Example 7, the title compound (305 mg, 89 95) was obtained as a white powder from the compound of Auxiliary Example 34 (370 mg, 0.968 mmol), 8M aqueous sodium hydroxide solution (1 ml ) and ethanol (7 ml).

"H-NMR (300 MHz, DMSO-av) δ: 2.28 (With H, s), 3.81 (With H, s), 3.86 (With H, s), 5.60 (2 H , c), 6.581 N, c), 1.61(2 N, t, U-7.4 Hu), 7.74 (1 N, t, U-7.3 Hu), 8.11 (2 N , d, 9-7.7 Hz), 12.50 (1 N, w s).

Auxiliary Example 36

Production of methyl (22)-3-aminopenta-2-enoate

EC of MN,

A mixture of methyl 3-oxovalerate (75.0 g, 576 mmol), ammonium acetate (222 g, 2.88 mol) and methanol (750 mL) was stirred at room temperature for 3 days. The mixture was concentrated under reduced pressure, water (500 ml) was added to the residue and the mixture was extracted with ethyl acetate (200 ml). The extract was washed with saturated saline, dried over magnesium sulfate, concentrated under reduced pressure and dried to give the title compound (68.5 g, 92 95) as a pale yellow oil. "H-NMR (300 MHz, DMSO-av) 6: 1.06 (Z H, t, 9U-7.6 Hz), 2.09 (2 H, k, 9U-7.6 Hz), 3, 49 (Z H, s), 4.34 (IN, s), 6.94 (1H, s), 7.72 (1H, w s).

Auxiliary Example 37

Preparation of ethyl b-ethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylatone

Eh Mo

N

To a solution of the compound of Auxiliary Example 36 (50.0 g, 387 mmol) and diethyl malonate (58.8 ml, 387 mmol) in ethanol (400 ml) was added 2095 solution (133 g) of sodium ethoxide in ethanol and the mixture was stirred at 150 C for 15 hours with ethanol evaporation. After cooling, the resulting solid was collected by filtration, washed with ethyl acetate and dissolved in water. The insoluble material was filtered off, the filtrate was acidified with 5M hydrochloric acid, and the precipitated solid was collected by filtration. The resulting solid was washed using water and ethyl acetate-hexane to give the title compound (36.4 g, 45 95) as a white powder. "H-NMR (300 MHz, DMSO-α) 5: 1.12 (3 N, t, 9U-7.6 Hz), 1.26 (3 N, t, 9-71 Hu), 2.42 ( 2 N, k, 9-7.6 Gu), 4.25 (2 N, k, 957.0 Gu), 5.79 (1 N, s), 11.37 (1 N, shs), 12, 57 (1 N, p.).

Auxiliary Example 38

Preparation of ethyl 4-chloro-6-ethyl-2-oxo-1,2-dihydropyridine-3-carboxylate

SI

EE M o

N

A mixture of the compound of Auxiliary Example 37 (15.0 g, 71.0 mmol) and phosphorus oxychloride (19.9 ml, 213 mmol) was stirred at 80 "C for 30 minutes. The mixture was concentrated under reduced pressure, ice water and precipitated the solid was collected by filtration and washed with water and ethyl acetate to give the title compound (9.80 g, 60 95) as a white solid." H-NMR (300 MHz, DMSO-α) 6:1, 15 (3 N, t, 9U-7.5 Hz), 1.26 (3 N, t, 9-7.0 Hz), 2.44-2.55 (2 N, m), 4.25 ( 2 N, k, 97.1 Gu), 6.26 (1 N, s), 12.28 (1 N, s).

Auxiliary Example 39

Preparation of ethyl 4-chloro-6-ethyl-2-oxo-1-(2-oxo-2-phenylethyl)-1,2-dihydropyridine-3-carboxylate

SI

Emo d

By a procedure similar to that given in Auxiliary Example 32, the title compound (1.00 g, 7 95) was obtained as a white powder from the compound of Auxiliary Example 38 (9.50 g, 41.4 mmol), potassium carbonate (13.7 g, 99.2 mmol), phenacyl bromide (9.88 g, 49.6 mmol) and DMF (100

ML). "H-NMR (300 MHz, DMSO-α) 5: 1.14 (3 N, t, 9U-7.4 Hz), 1.24 (3 N, t, 9-71 Hu), 2.62 ( 2 N, k, 9-74 Hu), 4.25 (2 N, k, 957.1 Hu), 5.61 (2 N, s), 6.44 (1 N, s), 7.54- 7.66 (2 N, m), 7.70-7.79 (1 N, m), 8.05-8.13 (2 N, m).

Auxiliary Example 40

Preparation of ethyl b-ethyl-3-hydroxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo|3,2-c|Ipyridine-2 -CO carboxylate,

Wow

Oh Mo

I

A mixture of the compound of Auxiliary Example 39 (950 mg, 2.73 mmol), sarcosine ethyl ester hydrochloride (839 mg, 5.46 mmol), triethylamine (2.27 mL, 16.4 mmol) and ethanol (10 mL) was stirred at 80 "C for 10 hours, then triethylamine (2.27 ml, 16.4 mmol) was added and the mixture was stirred at 100 "C for 15 hours. After cooling, water was added to the reaction mixture and the mixture was acidified with 1M hydrochloric acid and extracted with ethyl acetate. The extract was successively washed with water and saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluate; ethyl acetate/methanol--10/1) to give the title compound (698 mg, 67 95) as a brown solid. "H-NMR (300 MHz, DMSO-α) 5: 1.18 (3 N, t, 9U-7.4 Hz), 1.31 (3 N, t, 9-7.1 Hu), 2, 56 (2 N, k, 9-7.6 Hz), 3.80 (З3Н, s), 4.30 (2 N, k, U-7.2 Hz), 5.55 (2 N, s) , 6.43 (1 N, s), 7.60 (2 N, t, 9U-7.6 Hz), 7.68-7.79 (1 N, m), 8.00-8.21 ( 2 N, m), 8.90 (1 N, s).

Auxiliary Example 41

Preparation of ethyl b-ethyl-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo|3,2-c|Ipyridine-2 -carboxylate

Me. So,

M zhi 7 Ohme

E mo x

By a procedure similar to that given in Auxiliary Example 6, the title compound (156 mg, 23 95) was obtained as a white powder from the compound of Auxiliary Example 40 (650 mg, 1.70 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.19 (3 H, t, U-7.3 Hz), 1.30 (Z H, t, U-7.1 Hu), 2, 58(2 N, k, 9-7.4 Gu), 3.84(3N, s), 385(3N, s), 4.27 (2 NN, k, 9-7.0 Hz), 5, 58(2 N, s), 6.50 (1 N, s), 7.61 (2 N, t, 9-7.6 Gu), 7.67-7.82 (1 N, m), 8 ,03-8,19 (2 N, m).

Auxiliary Example 42

Preparation of b-ethyl-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo|3,2- c|Ipyridine-2- carboxylic acid

Me. Sleep

Moscow State University

EN MO

;

By a procedure similar to that given in Auxiliary Example 7, the title compound (110 mg, 79 95) was obtained as a white powder from the compound of Auxiliary Example 41 (150 mg, 0.378 mmol). "H-NMR (300 MHz, DMSO-av) 6: 1.19 (3 N, t, 9U-7.3 Hz), 2.57 (2 N, k, 9-7.3 Gu), 3, 84 (Z H, s), 3.85 (Z H, s), 5.58 (2 H, s), 6.48 (1 H, s), 7.61 (2 H, t, 9U-7 .6 Hz), 7.67-7.86 (1 N, m), 7.97-8.31 (2 N, m), 12.51 (1 N, w s).

Auxiliary Example 43

Preparation of 3-ethoxy-1,6-dimethyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolyl3,2-pyridine-2-carboxylate. Me. SOEI

University of OEI

Me Mo i

By a procedure similar to that given in Auxiliary Example 6, the title compound (560 mg, 52 95) was obtained as a white powder from the compound of Auxiliary Example 33 (1.00 g, 2.71 mmol) and iodate (326 μl , 4.07 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.24 (Z H, t, 9U-7.0 Hz), 1.30 (3 H, t, 9-71 Hu), 2.28 ( 3 N, s), 3.81 (Z N, s), 415 (2 NN, k, 9-7.0 Hz), 426 (2 N, k, 9-71 Hz), 5.60 (2 N , s), 6.58 (1 N, s), 7.61 (2 N, t, 9-7.6 Hz), 7.69-7.18 (1 N, m), 8.06-8 ,14 (2 N, m).

Auxiliary Example 44

Preparation of 3-ethoxy-1,6-dimethyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolyl3,2-c|Ipyridine-2-carboxylic acid

Me. sOo,n their zh og

Me M'O0 x

By a procedure similar to that given in Auxiliary Example 7, the title compound (380 mg, 74 95) was obtained as a white powder from the compound of Auxiliary Example 43 (550 mg, 1.39 mmol). "H-NMR (300 MHz, DMSO-av) 6: 1.22 (3H, t, 9U-7.0 Hz), 2.28(3H, s), 3.81 (3H, s), 4 ,16 (2 N, k, U-7.0

Gu, 5.60 (2 N, s), 6.57 (1 N, s), 7.61 (2 N, t, 9-7.6 Hz), 7.69-7.79 (1 N, m), 8.03-8.16 (2 N, m), 12.38 (1 N, w s).

Auxiliary Example 45

Preparation of ethyl 1,6-dimethyl-4-oxo-5-(2-oxo-2-phenylethyl)-3-propoxy-4,5-dihydro-1H-pyrrolo|3,2-sipyridine-2-carboxylate ok SOI schu (c)

Me! To Me and

By a procedure similar to that given in Supplementary Example 6, the title compound (152 mg, 1895) was prepared as a white powder from the compound (750 mg, 2.04 mmol)

Auxiliary Example 33 and 1-bromopropane (277 μl, 3.05 mmol). "H-NMR (300 MHz, DMSO-α) 6: 0.94 (Z H, t, 9U-7.5 Hz), 1.30 (Z H, t, Y-7.1 Hu), 1, 57-1.73 (2 N, m), 2.28 (ZH, s), 3.80 (3 N, s), 4.08 (2 N, t, 9-6.5 Hz), 4, 26 (2 N, k, 9U-7.1 Hz), 5.60 (2 N, s), 6.58 (1 N, s), 7.56-7.66 (2 N, m), 7 .69-7.78 (1 N, m), 8.06-8.15 (2 N, m).

Auxiliary Example 46

Preparation of 1,6-dimethyl-4-oxo-5-(2-oxo-2-phenylethyl)-3-propoxy-4,5-dihydro-1H-pyrrolo|3,2-c|Ipyridine-2-carboxylic acid

Me. sleep

M s 10) yin

Me Mo Me d

By a procedure similar to that given in Auxiliary Example 7, the title compound (105 mg, 81 95) was obtained as a white powder from the compound of Auxiliary Example 45 (140 mg, 0.341 mmol). "H-NMR (300 MHz, DMSO-α) 6: 0.88-0.94 (With H, m), 1.58-1.67 (2 H, m), 2.27 (With H, s ), 3.81 (With N, s), 4.08 (2 N, t, U-6.6 Hz), 5.60 (2 N, s), 6.57 (1 N, s), 7 .55-7.65 (2 N, m), 7.69-7.77 (1 N, m), 8.06-8.14 (2 N, m).

Auxiliary Example 47

Preparation of ethyl 6b-ethyl-3-ethoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo|3,2-

Cypyridine-2-carboxylate

Me сСОЖжж

Lk - EE

Oh Mo

A mixture of the compound of Auxiliary Example 40 (330 mg, 0.863 mmol), potassium carbonate (715 mg, 5.18 mmol), iodate (138 μl, 1.73 mmol), and DMF (5 mL) was stirred at room temperature for 15 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The extracts were combined, washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was collected by filtration and dried to give the title compound (189 mg, 46 95) as a white powder. "H-NMR (300 MHz, DMSO-α) 6: 1.13-1.35 (9 N, m), 2.57 (2 N, k, U-7.2 Gu), 3.84 (Z N, s), 4.10-4.19 (2 N, m), 426(2 N, Kk, 9-7.2 Gu), 5.58 (2 N, s), 6.49 (1 N , c), 7.61 (2 N, t, 9-7.6 Hz), 7.70-7.77 (1 N, m), 8.07-8.14 (2 N, m).

Auxiliary Example 48

Preparation of 3-ethoxy-b-ethyl-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrole|3,2- c|Ipyridine-2- carboxylic acid

Me so

M x - OB

E M OO ru

A solution of the compound of Auxiliary Example 47 (160 mg, 0.390 mmol) and an 8M aqueous solution of sodium hydroxide (1 ml) in ethanol (7 ml) was stirred at 60 "C for 1 hour. The reaction mixture was diluted with water, acidified with 6M hydrochloric acid and a precipitated solid collected by filtration. The resulting solid was washed with water and dried under reduced pressure to afford the title compound (74.0 mg, 50 95) as a white powder. "H-NMR (300 MHz, DMSO-α) 6:1 ,13-1.25 (6 N, m), 2.57 (2 N, Kk, U9-7.3 Hz), 3.84 (Z3N, s), 415 (2 NN, k, 9U-7, 0 Hu), 5.57 (2 N, s), 6.47 (1 N, s), 7.61 (2 N, t, U-7.5 Hu), 7.69-7.78 (1 N, m), 8.08-8.15 (2 N, m), 12.35 (1

N, w c).

Auxiliary Example 49

Preparation of ethyl 1,6b-dimethyl-4-oxo-5-(2-oxo-2-phenylethyl)-3-(2,2,2-trifluoroethoxy)-4,5-dihydro-1H-pyrrolo[3,2-c] Ipyridine-2-carboxylate

Me. SOE!

M hu u

E metom oso E d

A mixture of the compound of Sub-Example 33 (750 mg, 2.04 mmol), 1,1,1-trifluoro-2-iodoethane (603 μl, 6.12 mmol), potassium fluoride (119 mg, 2.04 mmol) and dimethyl sulfoxide ( 10 ml) was stirred at 100 "C for 15 hours. The reaction mixture was diluted with water and the mixture was extracted with ethyl acetate.

The extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on amino silica gel (eluate; ethyl acetate) to give the title compound (125 mg, 14 95) as a white solid. "H-NMR (300 MHz, DMSO-av) 5: 1.28 (3 H, t, 9U-7.2 Hu), 2.30 (Z H, s), 3.83 (Z H, s) , 4.19-4.31 (2 N, m), 4.84 (2 N, k, U-9.3 Hz), 5.64 (2 N, s), 6.66 (1 N, s ), 7.57-7.66 (2 N, m), 7.69-7.79 (1 N, m), 8.07-8.15 (2 N, m).

Auxiliary Example 50

Preparation of 1,6-dimethyl-4-oxo-5-(2-oxo-2-phenylethyl)-3-(2,2,2-trifluoroethoxy)-4,5-dihydro-1H-pyrrolo|3,2- c|Ipyridine-2-carboxylic acid

Mae Son

M

Sg p o E

She

Me mM'o E r:

A solution of the compound of Auxiliary Example 49 (110 mg, 0.244 mmol) and an 8M aqueous solution of sodium hydroxide (1 mL) in ethanol (7 mL) was stirred at 60 °C for 1 hour. The reaction mixture was diluted with water and acidified with 6M hydrochloric acid, and the precipitated solid the material was collected by filtration. The resulting solid was washed with water and dried under reduced pressure to give the title compound (78.0 mg, 76 95) as a white powder. "H-NMR (300 MHz, DMSO-α) 6: 2.29 (Z H, s), 3.83 (Z H, s), 4.82 (2 H, k, U-9.3 Gu), 5.63 (2 H, s), 6.64 (1

N, s), 7.61 (2 N, t, U-7.6 Hz), 7.70-7.78 (1 N, m), 8.07-8.15 (2 N, m), 12.57 (1H, w s).

Auxiliary Example 51

Preparation of ethyl (22)-3-aminoheco-2-enoate pu

Me MA,

By a procedure similar to that given in Auxiliary Example 36, the title compound (109 g, quant.) was obtained as a pale yellow oil from ethyl 3-oxohexanoate (100 g, 632 mmol), ammonium acetate (244 g, 3.16 mmol) and methanol (750 ml). "H-NMR (300 MHz, DMSO-av) 6: 0.87 (With H, t, 9U-7.4 Hz), 1.11-1.17 (With H, m), 1.42-1 .58 (2 N, m), 2.00-2.07 (2 N, m), 3.96 (2 N, k, 9-7.2 Hz), 4.30 (1 N, s), 6.90 (1 N, w s), 7.73 (1 N, w s).

Auxiliary Example 52

Production of ethyl 4-hydroxy-2-oxo-6-n-propyl-1,2-dihydropyridine-3-carboxylate

ON

Me M o

N

By a procedure similar to that given in Auxiliary Example 37, the title compound (27.5 g, 34 95) was obtained as a white powder from the compound of Auxiliary Example 51 (50.0 g, 0.387 mmol), diethyl malonate (58, 8 ml, 387 mmol) and ethanol (400 ml). "H-NMR (300 MHz, DMSO-α) 6: 0.87 (3 H, t, 9U-7.4 Hz), 1.26 (Z H, t, 9-7.2 Hu), 1, 49-1.65 (2 N, m), 2.38 (2 N, t), 4.252 N, k, 9U9-7.0 Hz), 5.79 (1 N, s), 11.37 (1 H, c), 12.56 (1 H, c).

Auxiliary Example 53

Preparation of ethyl 4-chloro-2-oxo-6-propyl-1 2-dihydropyridine-3-carboxylate

SI va

Me M'Oo

N

A mixture of the compound of Auxiliary Example 52 (37.0 g, 164 mmol) and phosphorus oxychloride (45.9 mL, 493 mmol) was stirred at 80 °C for 30 minutes. The mixture was concentrated under reduced pressure and ice water was added to the residue. The resulting solid collected by filtration and washed with water and ethyl acetate to give the title compound (17.6 g, 44 95) as a white solid." H-NMR (300 MHz, DMSO-α) 6: 0.87 (Z H, t, 9U-7.4 Hz), 1.26 (With H, t, 9U-7.1 Gu, 1.52-1.65 (2 H, m), 2.40- 2А48(2H, m), 4.25 (2H, k, 9U-7.1 GG), 627 (1H, s), 1217 (IN, w s).

Auxiliary Example 54

Preparation of ethyl 4-chloro-2-oxo-1-(2-oxo-2-phenylethyl)-β6-propyl-1 2-dihydropyridine-3-carboxylate

SI beer

Me M'E rya

By a procedure similar to that given in Auxiliary Example 4, the title compound (7.15 g, 28 95) was obtained as a white powder from the compound of Auxiliary Example 53 (17.0 g, 69.8 mmol), sodium hydride (60 95 in oil, 3.07 g, 76.7 mmol), phenacyl bromide (16.7 g, 83.8 mmol) and

DMF (150 ml). "H-NMR (300 MHz, DMSO-α) 6: 0.91 (With H, t, 9U-7.3 Hz), 1.24 (With H, t, 97.1 Hu), 1.47- 1.64 (2 N, m), 2.55-2.66 (2 N, m), 4.24 (2 N, k, 9-71 Gu), 5.594 (2 N, s), 6.47 ( 1 N, s), 7.612 N, t, 9-76 Gu), 7.70-7.80 (1 N, m), 8.06-8.17 (2 N, m).

Auxiliary Example 55

Preparation of /3-hydroxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-b-propyl-4,5-dihydro-1H-pyrrolo|3,2- cIpyridine-2-carboxylate

Me CO m x - TON

Me Mo y

A mixture of the compound of Auxiliary Example 54 (7.00 g, 19.3 mmol), sarcosine ethyl ester hydrochloride (5.94 g, 38.7 mmol), triethylamine (29.7 ml, 193 mmol) and ethanol (100 ml) was stirred for 2 days under reflux. The mixture was concentrated under reduced pressure, water (200 ml) was added to the residue and the mixture was acidified with 5M hydrochloric acid (3 ml).

The resulting solid was collected by filtration and washed with water and hexane-ethyl acetate to give the title compound (5.70 g, 74 95) as a white solid. "H-NMR (300 MHz, DMSO-α) 6: 0.92 (Z H, t, 9U-7.3 Hz), 1.31 (Z H, t, Y-7.1 Hu), 1, 50-1.65 (2 N, m), 2.49- 2.57 (2 N, m), 3.78 (Z H, s), 4.30 (2 N, k, U-7.1 Hz), 5.52 (2 N, s), 6.45 (1 N, s), 7.60 (2 N, t, 9U-7.5 Hz), 7.68-7.78 (1 N , m), 8.07-8.15 (2 N, m), 8.90 (1 N, w s).

Auxiliary Example 56

Preparation of 3-ethoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-6-propyl-4,5-dihydro-1H-pyrrolo|3,2- cIpyridine-2-carboxylate

Me, SOZHzhI

LE

- OB

Me Ko,

WITH

A mixture of the compound of Auxiliary Example 55 (1.00 g, 8.08 mmol), diethyl sulfate (397 μL, 3.03 mmol), potassium carbonate (1.05 g, 7.57 mmol), and acetone (20 mL) was stirred for 15 hours under reflux. Water (30 mL) was added to the mixture and the precipitated solid was collected by filtration and washed with water and ethyl acetate-hexane to give the title compound (876 mg, 82 95) as a white solid. "H-NMR (300 MHz, DMSO-α) 6: 0.93 (3 H, t, U-7.4 Hz), 1.23 (Z H, t, 9-7.0 Hz), 1, 30 (With H, t, 9-71 Gu), 1.52-1.66 (2 H, m), 2.51-2.58 (2 NN, m), 3.83 (With H, s) , 4.14 (2 N, k, 957.1 Gu), 4.26 (2 N, k, U-7.1 Hz), 5.54 (2

N, c), 6.51 (1 N, c), 7.61 (2 N, t, U-7.6 Gu), 7.69-7.77 (1 N, m), 8.08- 8.15 (2 N, m).

Auxiliary Example 57

Preparation of 3-ethoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-6-propyl-4,5-dihydro-1H-pyrrolo|3,2- c|Ipyridine-2- carboxylic acid

Me, DREAM

M them - OB

Me Mo

H

A solution of the compound of Auxiliary Example 56 (850 mg, 2.00 mmol) and an 8M aqueous solution of sodium hydroxide (2 ml) in ethanol (14 ml) was stirred at 60 "C for 30 minutes. The reaction mixture was diluted with water, acidified with 5M hydrochloric acid and precipitated the solid was collected by filtration. The resulting solid was washed with water and dried under reduced pressure to afford the title compound (705 mg, 89 95) as a white powder. "H-NMR (300 MHz, DMSO-α) 6:0 .93 (With N, t, 9U-7.4 Hz), 1.21 (3 N, t, U-7.0 Gu), 1.50-1.66 (2 N, m), 2.50 - 2.58 (2 N, m), 3.83 (Z H, s), 4.15 (2 N, k, U-7.1 Hz), 5.54 (2 N, s), 6, 50 (1 N, s), 7.61 (2 N, t, 9-76 Hz), 7.69-7.78 (1 N, m), 8.08-8.16 (2 N, m) , 12.42 (1H, w s).

Auxiliary Example 58

Preparation of ethyl b-ethyl-3-(2-fluoroethoxy)-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo|3,2-s Ipyridine-2-carboxylate

Me coOzh

LE

- o

EE mo E x

By a procedure similar to that given in Auxiliary Example 6, the title compound (649 mg, 77 95) was obtained as a white powder from the compound of Auxiliary Example 40 (750 mg, 1.96 mmol), OVIi (440 μl, 2 .94 mmol) and 1-fluoro-2-iodoethane (512 mg, 2.94 mmol). "H-NMR (300 MHz, DMSO-α) 5: 1.19 (3 N, t, 9U-7.3 Hz), 1.30 (3 N, t, 9-71 Hu), 2.58 ( 2 N, k, 9-7.3 Gu), 3.85(3N, s), 4.26 (2 N, k, 957.1 Gu), 4.32-4.36 (1 N, m) , 4.42-4.47 (1 N, m), 4.53-4.59 (1 N, m), 4.69-4.75 (1

N, m), 5558(2N, s), 6.51(1 N, s), 7.61(2 N, t, 9-76 Hz), 7.70-7.77 (1 N, m) , 8.08-8.14 (2 N, m).

Auxiliary Example 59

Preparation of b-ethyl-3-(2-fluoroethoxy)-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo|3,2-c| Ipyridine-2-carboxylic acid

Me sl

M

-70 -

Emo E x

A solution of the compound of Auxiliary Example 58 (620 mg, 1.45 mmol) and an 8M aqueous solution of sodium hydroxide (1 ml) in ethanol (7/7 ml) was stirred at 60 "C for 30 minutes. The reaction mixture was diluted with water, acidified with 5M hydrochloric acid and the precipitated solid was collected by filtration. The resulting solid was washed with water and dried under reduced pressure to afford the title compound (470 mg, 56 95) as a white powder. "H-NMR (300 MHz, DMSO-α) 5 : 1.19 (Z H, t, 9U-7.4 Gu), 2.58 (2 H, k, 9-74 Hz), 3.85 (Z H, s), 4.32-4.36 (1 N, m), 4.42-4.47 (1 N, m), 4.54-4.59 (1 N, m), 4.70-4.74 (1 N, m), 5 .58 (2 N, s), 6.50 (1 N, s), 7.61 (2 N, t, 9-7.6 Hz), 7.70-7.77 (1 N, m), 8.09-8.15 (2 N, m), 12.48 (1 N, w s).

Auxiliary Example 60

Preparation of ethyl b-ethyl-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-3-(2,2,2-trifluoroethoxy)-4,5-dihydro-1H-pyrroloyi3,2- c|Ipyridine-2-carboxylate

Me SO

Ms. E

EE MmM'o E

H

A mixture of the compound of Auxiliary Example 40 (1.00 g, 2.61 mmol), 1,1,1-trifluoro-2-iodoethane (1.29 mL, 13.1 mmol), cesium carbonate (4.27 g, 13, 1 mmol) and dimethyl sulfoxide (10 ml) were stirred at 100 C for 5 hours. The reaction mixture was filtered, the filtrate was diluted with 1M hydrochloric acid (30 ml) and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by amino silica gel chromatography (eluent; hexane/ethyl acetate-9/1-0/10) to give the title compound (278 mg, 23 95) as a white solid. "H-NMR (300 MHz, DMSO-α) 6: 1.19 (3 N, t, U-7.4 Hz), 1.28 (3 N, t, U-7.1 Hu), 2, 59(2 N, k, 9-7.4 Hu), 3.86 (Z H, s), 4.26 (2 N, k, 9U-7.1 Hu), 4.83 (2 N, k , U-9.3 Hz), 5.62 (2 N, s), 6.56 (1 N, s), 7.61 (2 N, t, 9-7.5

Hz), 7.70-7.78 (1 N, m), 8.08-8.14 (2 N, m).

Auxiliary Example 61

Preparation of b-ethyl-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-3-(2,2,2-trifluoroethoxy)-4,5-dihydro-1H-pyrrolo|3, 2-c|Ipyridine-2-carboxylic acid

Me. I sing my dream

IS

EMO E d

A solution of the compound of Auxiliary Example 60 (270 mg, 0.581 mmol) and an 8 M aqueous solution of sodium hydroxide (1 ml) in ethanol (7 ml) was stirred at 60 "C for 1 hour. The reaction mixture was diluted with water, acidified with 5 M hydrochloric acid and the precipitated solid was collected by filtration. The resulting solid was washed with water and dried under reduced pressure to give the title compound (235 mg, 93 95) as a white powder. "H-NMR (300 MHz, DMSO-α) 6: 1.19 (With H, t, U-7.4 Hz), 2.58(2 H, k, 9-74 Gu), 3.86 (With H, s), 4.82 (2 H,

Kk, U-9.2 Hz), 5.61 (2 N, s), 6.54 (1 N, s), 7.61 (2 N, t, 9-7.6 Gu), 7.70 -7.77 (1 N, m), 8.07-8.16 (2 N, m), 12.74 (IN, w s).

Auxiliary Example 62

Preparation of ethyl 4-chloro-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxylate

SI

M' o

N

A mixture of ethyl 4-hydroxy-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxylate (26.0 g, 110 mmol) and phosphorus oxychloride (51.3 ml) was stirred at 130 "С for 1.5 hours. After cooling, the reaction mixture was concentrated under reduced pressure and ice was added to the residue. The mixture was neutralized with saturated sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was successively washed with saturated sodium hydrogencarbonate solution, water and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was collected by filtration and washed with ethyl acetate-hexane to give the title compound (4.65 g, 17 9g) as a white solid. "H-NMR (300 MHz, DMSO- av) 6: 1.25 (With N, t, 9-71 Hz), 1.61-1.74 (4 N, m), 2.37-2.45 (2 N, m), 2.51 -2.57 (2 N, m), 4.24 (2 N, k, 9-7.2 Hz), 12.09 (1 N, s).

Auxiliary Example 63

Production of ethyl 4-chloro-2-oxo-1-(2-oxo-2-phenylethyl)-1,2,5,6,7,8-hexahydroquinoline-3-carboxylate

SI m o ;

By a procedure similar to that given in Auxiliary Example 4, the title compound (710 mg, 16 95) was obtained as a white powder from the compound of Auxiliary Example 62 (3.00 g, 11.7 mmol), sodium hydride (60 95 in oil, 516 mg, 12.9 mmol) and phenacyl bromide (2.57 g, 12.9 mmol). "H-NMR (300 MHz, DMSO-av) 6: 1.25 (ZN, t, 9U-7.1 Gu), 1.60-1.80 (AN, m), 2.50-2.65 (4H, m), 4.26 (2H, k, 9-71 Hu), 5.66 (2H, s), 7.61 (2H, t, U-7.4 Hu), 7.74 (1H , t, U-7.4 Gu), 8.09 (2H, d, 9-74 Hz).

Auxiliary Example 64

Preparation of 3-hydroxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5,6,7,8,9-hexahydrothienoic 3,2-c|quinoline-2-carboxylate

CO from them

Mo d

By a procedure similar to that given in Auxiliary Example 5, the title compound (751 mg, 100 95) was obtained as a white powder from the compound of Auxiliary Example 63 (690 mg, 1.85 mmol), 20 95 of a solution (1, 26 g, 3.69 mmol) of sodium ethoxide in ethanol, ethyl thioglycolate (486 μL, 4.43 mmol) and ethanol (15 mL). "H-NMR (300 MHz, DMSO-av) 6: 1.29 (ZN, t, 9-7.0 Gu), 1.65-1.85 (AN, m), 2.50-2.65 (4H, m), 4.28 (2H, k, 9U-7.0 Hz), 5.72 (2H, s), 7.62 (2H, t, U-7.7 Gu), 7.73 -7.78 (1H, m), 8.10-8.13 (2H, m), 10.39 (1H, s).

Auxiliary Example 65

Preparation of 3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5,6,7,8,9-hexahydrothieno|3,2-c)quinoline-2-carboxylate

SSOOE

With and; I'm Ome

Mo;

By a procedure similar to that given in Auxiliary Example 6, the title compound (238 mg, 31 95) was obtained as a white powder from the compound of Auxiliary Example 64 (740 mg, 1.80 mmol), iodomethane (168 μl, 2 .70 mmol), OVI (404 μL, 2.70 mmol) and DMF (15 mL). "H-NMR (300 MHz, DMSO-av) 6: 1.31 (ZH, t, 9U-7.0 Hz), 1.65-1.85 (4H, m), 2.45-2.65 (AN, m), 3.89 (ZH, s), 4.29 (2H, k, 9-7.0 Hz), 5.67 (2H, s), 7.62 (2H, t, 9- 74 Hz), 7.75 (IN, t, U-7.4 Hz), 8.11 (2H, d, 9-74 Hz).

Auxiliary Example 66

Preparation of 3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5,6,7,8,9-hexahydrothieno|3,2-c)quinoline-2-carboxylic acid

WITH

IN

Mo

WITH

A solution of the compound of Auxiliary Example 65 (220 mg, 0.517 mmol) and an 8M aqueous solution of sodium hydroxide (1 ml) in ethanol (/7 ml) was stirred at 60 C for 1 hour. The reaction mixture was acidified with EM hydrochloric acid (1.5 mL) and the precipitated solid was collected by filtration. The resulting solid was washed with water and dried under reduced pressure to give the title compound (162 mg, 79 95) as a white powder. "H-NMR (300 MHz, DMSO-α) 5: 1.66-1.88 (4H, m), 2.52-2.61 (4H, m), 3.86 (ZH, s), 5 .66 (2H, s), 7.62 (2H, t, U9-7.6 Hz), 7.70-7.79 (1H, m), 8.03-8.11 (2H, m), 13.12 (1H, p).

Auxiliary Example 67

Preparation of ethyl 4-chloro-3-hydroxy-b-methylthienoi3,2-s|Ipyridine-2-carboxylate so

STILL t on ra

Me M SI

Potassium carbonate (8.85 g, 64.1 mmol) and ethyl thioglycolate ( 4.68 ml, 42.7 mmol), and the mixture was stirred for 15 hours under reflux. The reaction mixture was diluted with water (150 ml), 6M hydrochloric acid (15 ml) was added and the mixture was stirred for 30 minutes. The resulting solid was collected by filtration, washed using water and ethanol-diisopropyl ether (1/1), and dried under reduced pressure to give the title compound (10.9 g, 94 95) as a white powder. "H-NMR (300 MHz, DMSO-α) 5: 1.32 (ZH, t, 9-7.1 Hu), 2.54 (ZH, s), 4.36 (2H, k, 9-71 Hz), 7.87 (1H, s), 10.75 (1H, s).

Auxiliary Example 68

Production of ethyl 4-chloro-3-ethoxy-b-methylthieno|3,2-s|pyridine-2-carboxylate

SOY

STILL in OB zho

Me M SI

By a procedure similar to that given in Auxiliary Example 6, the title compound (4.30 g, 78 95) was obtained as a white powder from the compound of Auxiliary Example 67 (4.97 g, 18.3 mmol), OVI ( 4.10 ml, 27.4 mmol) and iodate (2.19 ml, 27.4 mmol). "H-NMR (300 MHz, DMSO-av) 6: 1.33 (ZN, t, 9U-7.2 Hz), 1.43 (ZN, t, 9U-7.1 Hu), 2.54 ( ЗН, с), 4.25 (2Н, к, 9У-7.0 Hz), 4.34 (2Н, к, 9-71 Hz), 7.92 (1Н, с).

Auxiliary Example 69

Preparation of 4-chloro-3-ethoxy-6-methylthieno|3,2-s|Ipyridine-2-carboxylic acid son and p- (Fi rai

Me M SI

A mixture of a solution of the compound of Auxiliary Example 68 (4.30 g, 14.3 mmol) and an 8M aqueous solution of sodium hydroxide (15 ml) in THF (22 ml)-ethanol (22 ml) was stirred for 5 hours at reflux . The reaction mixture was acidified with 6M hydrochloric acid (22 mL) and the precipitated solid residue was collected by filtration. The resulting solid was washed with water and dried under reduced pressure to give the title compound (3.80 g, 97 95) as a white powder. "H-NMR (300 MHz, DMSO-α) 5: 1.40 (ZH, t, 9-6.9 Hu), 2.54 (ZH, s), 4.26 (2H, k, 9U-6 .9 Hz), 7.90 (1H, s), 13.65 (1H, s).

Auxiliary Example 70

Preparation of 4-chloro-M-(2-(diethylamino)ethyl|-3-ethoxy-M,b-dimethylthienoyl3,2-c|Ipyridine-2-carboxamide

EE h

M-EE (9) th-

M,

Kh Mes (9154, nt

Me M si

By a method similar to the method given in Example 25, the title compound (800 mg, 59 95) in the form of a colorless oil from the compound of Auxiliary Example 69 (1.00 g, 3.68 mmol) and M, M-diethyl-M of '-methylethane-1,2-diamine (773 μl, 4.78 mmol). "H-NMR (300 MHz, DMSO-α) 6: 0.65-1.10 (6H, m), 1.33 (ZH, t, U-6.9 Hz), 2.20-2.70 (6Н, m), 2.53 (ЗН, с), 3.04 (ЗН, с), 3.35-3.65 (2Н, m), 4.05-4.20 (2Н, m), 7.89 (1H, s).

Auxiliary Example 71

Production of ethyl 4-chloro-3-hydroxy-6b,7-dimethylthieno|3,2-s|Ipyridine-2-carboxylate

CO. more

Me | t he paradise

Me MCCI 95 solution (1.73 g, 5.08 mmol) of sodium ethoxide in ethanol was diluted with ethanol (5 mL) and ethyl thioglycolate (610 mg, 5.08 mmol) was added. Ethyl 2,4-dichloro-5,6-dimethylpyridine-3-carboxylate (630 mg, 2.54 mmol) was added to the mixture and the mixture was stirred at room temperature for 18 hours.

2M hydrochloric acid (3 ml) was added to the reaction mixture and the mixture was partitioned between saturated saline solution and ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated.

The resulting solid was washed using diisopropyl ether-hexane and dried under reduced pressure to give the title compound (374 mg, 52 95) as a white powder. "H-NMR (300 MHz, SOS") 6: 1.43 (ZN, t, 9U-7.2 Hz), 2.40 (ZN, s), 2.61 (ZN, s), 4.44 (2H, k, U-7.2 Hu), 10.63 (1H, s).

Auxiliary Example 72

Preparation of ethyl 4-chloro-3-ethoxy-6b,7-dimethylthieno|3,2-c|Ipyridine-2-carboxylate

SOEI

MORE

Me | sh- OEI pc

Me M SI

By a procedure similar to that given in Auxiliary Example 6, the title compound (350 mg, 91 95) was obtained as a white solid from the compound of Auxiliary

Example 71 (350 mg, 1.22 mmol), OVI (380 mg, 2.02 mmol) and iodethane (315 mg, 2.02 mmol). "H-NMR (300 MHz, SOSIz) 5: 1.43 (ZN, t, 9U-7.2 Hz), 1.54 (ZN, t, 9-7.2 Hz), 2.42 (ZN, s), 2.60 (ZH, s), 4.31 (2H, k, 9-7.2 Hz), 4.41 (2H, k, 9U-7.2 Hz).

Auxiliary Example 73

Preparation of 4-chloro-3-ethoxy-6,7-dimethylthieno|3,2-s|Ipyridine-2-carboxylic acid

Me | s og ay

Me M SI

A mixture of a solution of the compound of Auxiliary Example 72 (250 mg, 0.80 mmol) and a 4M aqueous solution of sodium hydroxide (2 ml) in THF (2 ml)-ethanol (1 ml) was stirred at room temperature for 18 hours. The reaction mixture was partitioned between 1M hydrochloric acid and ethyl acetate, and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (210 mg, 92 95) as a white solid. "H-NMR (300 MHz, DMSO-α) 5: 1.40 (ZN, t, 9-71 Hz), 2.40 (ZN, s), 2.53 (ZN, s), 4.25 ( 2H, k, 9-7.0 Hz).

Auxiliary Example 74

Preparation of 4-chloro-M-(2-(diethylamino)ethyl|-3-ethoxy-M,b,7-trimethylthienoi|3,2-c|Ipyridine-2-carboxamide

IS! h

M--ЕИ (c) и-

M,

Kz x Me

Me | i ОЙ рый

Me M SI

By a procedure similar to that of Example 25, the title compound (230 mg, 79 95) was obtained as a colorless oil from the compound of Auxiliary Example 73 (210 mg, 0.73 mmol) and M,M-diethyl-M' -methylethane-1,2-diamine (144 mg, 1.10 mmol). "H-NMR (300 MHz, SOSI") 6: 0.80-1.10 (6H, m), 1.42 (ZN, t, U-6.9 Hu), 2.30-2.50 ( 5Н, m), 2.60-2.80 (7Н, m), 3.19 (ЗН, с), 3.45-3.70 (2Н, m), 4.18 (2Н, k, 9- 7.0 Hz).

Auxiliary Example 75

Preparation of 3-hydroxy-6-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno|3,2-s|pyridine-2-carboxylate

SOEI

R by On what

Me M 0 -0

By a procedure similar to that given in Auxiliary Example 5, the title compound (8.31 g, 88 95) was obtained as a white powder from the compound of Auxiliary Example 32 (8.50 g, 25.5 mmol), ethyl thioglycolate ( 6.70 ml, 61.1 mmol), 20 95 solution (17.4 g, 51.0 mmol) of sodium ethoxide in ethanol and ethanol (100 ml). "H-NMR (300 MHz, DMSO-α) 5: 1.28 (ZH, t, 9-7.2 Hz), 2.33 (ZH, s), 4.27 (2H, k, 9-71 Hz), 5.71 (2H, s), 6.93 (1H, d, U-0.9 Hz), 7.62 (2H, t, 9-7.5 Hz), 7.69-7, 83 (1H, m), 8.01-8.21 (2H, m), 10.34 (1H, s).

Auxiliary Example 76

Preparation of 3-methoxy-6-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno|3,2-s|Ipyridine-2-carboxylate

CO

R p OMe

Me M OO d

A mixture of the compound of Auxiliary Example 75 (3.00 g, 8.08 mmol), dimethyl sulfate (4.58 mL, 48.4 mmol), potassium carbonate (3.35 g, 24.2 mmol), and acetone (60 mL) was stirred within 3 days under reflux. Water (120 mL) was added to the mixture and the precipitated solid was collected by filtration and washed with water, ethanol and ethyl acetate to give the title compound (2.45 g, 79 90) as a white solid. "H-NMR (300 MHz, DMSO-α) 6: 1.30 (ZN, t, U-7.1 Hu), 2.31 (ZN, s), 3.88 (ZN, s), 4, 28 (2H, k, U-7.2 Hz), 5.66 (2H, s), 6.85 (1H, d, U-0.8 Hz), 7.58-7.67 (2H, m ), 7.70-7.80 (1H, m), 8.06-8.15 (2H, m).

Auxiliary Example 77

Preparation of 3-ethoxy-b-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno|Y3,2-c|Ipyridine-2-carboxylate

CO

R

- o

Me M 'O d

By a procedure similar to that given in Auxiliary Example 6, the title compound (585 mg, 54 95) was obtained as a white powder from the compound of Auxiliary Example 75 (1.00 g, 2.89 mmol), OVIi (604 μl , 4.04 mmol) and iodoethane (323 μl, 4.04 mmol). "H-NMR (300 MHz, DMSO-α) 5: 1.23-1.35 (6H, m), 2.31 (ZH, s), 4.14 (2H, k, 9-7.0 Hz ), 4.27 (2H, k, 9-71 Hu), 5.67 (2H, s), 6.84 (1H, d, U-0.8 Hu), 7.57-7.67 (2H , m), 7.71-7.79 (1H, m), 8.07-8.15 (2H, m).

Auxiliary Example 78

Preparation of 3-methoxy-6-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno|3,2-s|Ipyridine-2-carboxylic acid son in p OoMe

Me M 0 x

By a procedure similar to that given in Auxiliary Example 7, the title compound (1.25 g, 67 95) was obtained as a white powder from the compound of Auxiliary Example 76 (2.00 g, 5.19 mmol), 8M aq. sodium hydroxide solution (3 ml) and ethanol (21 ml). "H-NMR (300 MHz, DMSO-α) 6: 2.31 (ZH, m), 3.86 (ZH, s), 5.66 (2H, s), 6.83 (1H, d, 9U -0.8 Hz), 7.58-7.68 (2H, m), 7.71-7.80 (1H, m), 8.08-8.17 (2H, m), 13.07 ( IN, w c).

Auxiliary Example 79

Preparation of sodium 3-ethoxy-b-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno|Y3,2-c|Ipyridine-2-carboxylic acid

R by o

Me M 0 x

By a procedure similar to that given in Auxiliary Example 7, the title compound (311 mg, 67 95) was obtained as a white powder from the compound of Auxiliary Example 77 (500 mg, 1.25 mmol), 8M aqueous sodium hydroxide solution ( 1 ml) and ethanol (7 ml). "H-NMR (300 MHz, DMSO-av) 6: 1.27 (ZH, t, U-7.0 Gu), 2.30 (ZH, s), 4.14 (2H, k, 9U-7 ,0 Hz), 5.66 (2H, s), 6.82 (1H, s), 7.58-7.66 (2H, m), 7.71-7.79 (1H, m), 8 ,08-8,17 (2H, m), 13,05 (IN, w s).

Auxiliary Example 80

Preparation of ethyl 4-hydroxy-1-methyl-2-oxo-1 2-dihydroquinoline-3-carboxylatone

M (c)

Me

To a solution of diethylmalonate (68.0 g, 0.425 mol) in DMF (400 mL) was added sodium hydride (66 95 in oil, 10.8 g, 0.30 mol) while cooling on ice, and the mixture was stirred at the same temperature for 5 minutes and at room temperature for 15 minutes. M-methyl anhydride (50.8 g, 0.287 mol) was added to the resulting mixture in small portions and the mixture was stirred at 1207 for 3 hours. Diisopropyl ether (500 mL) was added to the reaction mixture and the precipitated solid was collected by filtration and washed with diisopropyl ether. The resulting solid was suspended in a mixture of methanol (250 mL) and water (500 mL), 5M hydrochloric acid (60 mL) was added dropwise, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with water and concentrated under reduced pressure. The residue was washed with diisopropyl ether to give the title compound (41.4 g, 58 Vol). "H-NMR (300 MHz, SOSI") 6: 1.49 (ZH, t, 9-71 Hz), 3.66 (ZH, s), 4.51 (2H, k, 9-71 Hz), 7.23-7.30 (IN, m), 7.32 (1H, d, 9-8.7 Gu), 7.69 (1H, ddd, U-8.7, 7.1, 1.6 Gu), 8.19 (1H, dd, U-8.0, 1.6 Hz), 14.21 (1H, s).

Auxiliary Example 81

Preparation of ethyl 4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate

SI

M (in)

Me

A mixture of the compound of Auxiliary Example 80 (58.0 g, 0.235 mol) and phosphorus oxychloride (33 ml, 0.35 mol) was stirred at 110 °C for 30 minutes. The reaction mixture was concentrated under reduced pressure and ice water and ethyl acetate were added. Organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, 1M sodium hydroxide solution (3 times), and water and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-diisopropyl ether to give the title compound (47.7 g , 76 95). "H-NMR (300 MHz, SOS") 6: 1.42 (ZH, t, 9U-7.1 Hu), 3.73 (ZH, s), 4.48 (2H, k , 9-71 Hz), 7.35 (1H, ddd,

U-8.7, 71, 1.0 Hu), 7.40 (1H, d, 9U-8.7 Hz), 7.68 (1H, ddd, 9U-8.7, 71, 1.4 Hu ), 8.07 (1H, dd, U-8.0, 1.4 Hz).

Auxiliary Example 82

Preparation of 3-hydroxy-5-methyl-4-oxo-4,5-dihydrothieno3,2-c|quinoline-2-carboxylate

SO, EI

WITH

Their friend Y

M (c)

A Me 2095 solution (23.2 g, 68 mmol) of sodium ethoxide in ethanol was diluted with ethanol (70 mL), ethyl thioglycolate (9.0 mL, 82 mmol) was added to the resulting solution, and the mixture was stirred at room temperature for 10 minutes. The compound of Auxiliary Example 81 (9.04 g, 34.0 mmol) was added to the resulting mixture and the mixture was stirred at room temperature for 4 hours. The reaction mixture was neutralized with ice water and 2M hydrochloric acid (40 mL) while cooling on ice, and the mixture was extracted twice with chloroform. The combined organic layer was washed with water and saturated saline, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from THF-diisopropyl ether to give the title compound (9.12 g, 88 Vol). "H-NMR (300 MHz, SOS") 6: 1.42 (ZH, t, 9U-7.2 Hu), 3.76 (ZH, s), 4.41 (2H, k, 9-7, 2 Hz), 7.34 (1H, ddd, 9-7.9, 7.2, 0.68 Hz), 7.44-7.49 (1H, m), 7.63 (1H, ddd, 9U -8.6, 7.2, 1.4 Hz), 7.83 (1H, dd, 9-7.9, 1.4 Hz), 10.76 (IN, s).

Auxiliary Example 83

Preparation of 3-methoxy-5-methyl-4-oxo-4,5-dihydrothieno|3,2-s|quinoline-2-carboxylate

SOY

WITH

X them (in)

Me

OVIU (1.65 mL, 11 mmol) was added to a suspension of the compound of Auxiliary Example 82 (3.04 g, 10.0 mmol) in DMF (30 mL), and iodomethane (0.81 mL, 13 mmol) was added to the resulting solution at cooling on ice. The resulting mixture was stirred at room temperature for 21 hours, water was added, and the precipitated solid was collected by filtration. The obtained substance was dissolved in ethanol by heating, treated with activated carbon, filtered and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the mixture was washed with water and 0.5M sodium hydroxide solution, filtered through Celite (trade name), then washed twice with water and concentrated under reduced pressure. The residue was recrystallized from ethanol-diisopropyl ether to give the title compound (1.51 g, 48 Ob). "H-NMR (300 MHz, SOS") 6: 1.42 (ZN, t, 9U-7.2 Hz), 3.76 (ZN, s), 4.14 (ZN, s), 4.40 (2H, k, U-7.2 Hu), 7.24-7.31 (1H, m), 7.41 (1H, d, U-8.7 Hu), 7.59 (1H, ddd, U-8.7, 7.3, 1.5 Hz), 7.84 (1H, dd, U-8.1, 1.5 Gu).

Auxiliary Example 84

Preparation of 3-methoxy-5-methyl-4-oxo-4,5-dihydrothieno-3,2-siquinoline-2-carboxylic acid

SLEEP

WITH

X them (in)

Me

To a suspension of the compound of Auxiliary Example 83 (1.90 g, 5.99 mmol) in THF (20 mL) and ethanol (20 mL) was added 5M sodium hydroxide solution (2.4 mL, 12 mmol). The resulting mixture was stirred at room temperature for 1.5 hours. 1M hydrochloric acid (13 mL) was added to the reaction mixture and the precipitated solid was collected by filtration and recrystallized from methanol to give the title compound (1.14 g, 66 95).

"H-NMR (300 MHz, DMSO-av) 6: 3.66 (ZH, d, 9-1.1 Hu), 3.95 (ZH, s), 7.30-7.37 (1H, m ), 7.58-7.71 (2H, m), 7.94-8.00 (1H, m).

Auxiliary Example 85

Preparation of 3-(benzyloxy)-5-methyl-4-oxo-4,5-dihydrothieno|3,2-s|quinoline-2-carboxylate

SO, Hey

WITH

X co

M (in) -3

Me

OVIU (0.592 mL, 3.96 mmol) was added to a suspension of the compound of Auxiliary Example 82 (1.00 g, 3.30 mmol) in DMF (10 mL), and benzyl bromide (0.510 mL, 4.29 mmol) was added to the resulting solution.

The resulting mixture was stirred at room temperature for 15 hours. Ethyl acetate and water were added to the reaction mixture, and the organic layer was separated. The aqueous layer was extracted twice with ethyl acetate.

The combined organic layer was washed with water and 0.5M sodium hydroxide solution, filtered through

Celite (trade name), then washed with water and concentrated under reduced pressure.

The residue was purified by silica gel column chromatography (eluate; ethyl acetate/hexane-1/4-1/2-2/1) to give the title compound (980 mg, 75 b). "H-NMR (300 MHz, SOSIz) 6: 1.36 (ZH, t, 9-7.2 Hz), 3.78 (ZH, s), 4.36 (2H, k, 9-7.2 Hz), 5.34 (2H, s), 7.24-7 44 (BN, m), 7.59 (1H, ddd, 9U-8.6, 7.1, 1.4 Gu), 7, 63-7.69 (2H, m), 7.85 (1H, dd, 9U-7.8, 1.4 Hz).

Auxiliary Example 86

Preparation of 3-butoxy-5-methyl-4-oxo-4,5-dihydrothieno|3,2-s|quinoline-2-carboxylate

SO, Hey

WITH

X co

M (in) what

Me

To a suspension of the compound of Auxiliary Example 82 (1.00 g, 3.30 mmol) in DMF (10 ml) was added OVIU (0.592 ml, 3.96 mmol) and to the resulting solution was added 1-iodobutane (0.488 ml, 4.29 mmol) ).

The resulting mixture was stirred at room temperature for 15 hours. Ethyl acetate and water were added to the reaction mixture, the organic layer was separated and the aqueous layer was extracted twice with ethyl acetate.

The combined organic layer was washed with water and 0.5M aqueous sodium hydroxide solution, filtered through Celite (trade name), then washed with water and concentrated under reduced pressure.

The residue was purified by silica gel column chromatography (eluate; ethyl acetate/hexane-1/4-1/2-2/1) to give the title compound (1.05 g, 89 Vol). "H-NMR (300 MHz, SOSIz) 5: 1.01 (ZN, t, 9U-7.5 Hz), 1.42 (ZN, t, 9-7.2 Hz), 1.50-1, 66 (2H, m), 1.87-1.99 (2H, m), 3.74 (ZH, s), 4.28 (2H, t, U-6.6 Hz), 4.39 (2H , k, U-7.2 Hz), 7.27 (1H, ddd, U-8.0, 7.1, 0.9 Hu), 7.40 (IN, d, U-8.1 Hu) , 7.58 (1H, ddd, 9U-8.6, 7.1, 1.4 Gu), 7.81-7.86 (1H, m).

Auxiliary Example 87

Preparation of ethyl 5-methyl-4-oxo-3-(pyridin-4-ylmethoxy)-4,5-dihydrothienoyl 3,2-c)quinoline-2-carboxylate

SO, Hey

WITH

X so so A

Me

To a suspension of the compound of Auxiliary Example 82 (1.00 g, 3.30 mmol) in DMF (20 mL) was added OVO (1.18 mL, 7.89 mmol) and to the resulting solution was added 4-(chloromethyl)pyridine hydrochloride (704 mg, 4.29 mmol). The resulting mixture was stirred at room temperature for 18 hours, at 457 for 2 hours, and at 60 "C for 18 hours. OVO (1.18 mL, 7.89 mmol) and 4-(chloromethyl)pyridine hydrochloride (704 mg, 4 .29 mmol), and the mixture was stirred at 60 "C for 10 hours. Chloroform and water were added to the reaction mixture, the organic layer was separated and the aqueous layer was extracted with chloroform. The combined organic layer was washed with water and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-isopropyl ether to give the title compound (678 mg, 53 Vol). "H-NMR (300 MHz, SOSIz) 6: 1.35 (ZH, t, 9-7.2 Hz), 3.77 (ZH, s), 4.37 (2H, k, 9-7.2 Hz), 5.36 (2H, s), 7.27-7.34 (1H, m), 7.43 (1H, d, U-8.4 Gu), 7.58-7.65 (ZH , m), 7.86 (1H, dd, 9U-7.8, 1.2 Hz), 8.61-8.65 (2H, m).

Auxiliary Example 88

Preparation of ethyl 5-methyl-3-(2-morpholin-4-ylethoxy)-4-oxo-4,5-dihydrothienoic3,2-c|quinoline-2-carboxylate

SO, EI

WITH

Their sob

Mod

Me s (c)

OVIU (1.18 ml, 7.89 mmol) was added to a suspension of the compound of Auxiliary Example 82 (1.00 g, 3.30 mmol) in DMF (20 ml), and 4-(2-chloroethyl)morpholine hydrochloride was added to the resulting solution (798 mg, 4.29 mmol). The resulting mixture was stirred at room temperature for 17 hours. Chloroform and water were added to the reaction mixture, and the organic layer was separated. The aqueous layer was extracted with chloroform. The combined organic layer was washed with water and concentrated under reduced pressure.

The residue was recrystallized from ethyl acetate-diisopropyl ether to give the title compound (2.16 g, 85 U). "H-NMR (300 MHz, SOSI»z) 5: 1.41 (ZH, t, 9U-7.1 Hz), 2.63 (4H, w t, U-4.7 Hz), 2.96 (2H, t, 9-5.7 Gu), 3.72 (4H, w t, 9U-4.7 Hz), 3.74 (ZH, s), 4.38 (2H, k, 9-71 Hu), 4.43 (2H, t, U-5.7 Hz), 7.24-7.31 (1H, m), 7.40 (IN, d, U-8.5 Hu), 7, 58 (1H, ddd, 9U-8.5, 7.2, 1.5 Gu), 7.81-7.86 (1H, m).

Auxiliary Example 89

Preparation of ethyl 5-methyl-4-oxo-3-(tetrahydrofuran-2-ylmethoxy)-4,5-dihydrothieno|3,2-c)quinoline-2-carboxylate

СО, ЕЙ more (9) 1-5

M (c)

Me

OVIU (0.740 ml, 4.95 mmol) was added to a suspension of the compound of Auxiliary Example 82 (1.00 g, 3.30 mmol) in DMF (20 ml), and 2-(bromomethyl)tetrahydrofuran (90 95 content) was added to the resulting solution (0.617 mL, 4.9 mmol). The resulting mixture was stirred at 40 "C for 19 hours and at 807 for 23 hours, OVI (0.740 ml, 4.95 mmol) and 2-(bromomethyl)tetrahydrofuran (90 95 content) (0.617 ml, 4.9 mmol) were added, and the mixture was stirred at 80 "C for 66 hours. Ethyl acetate and water were added to the reaction mixture, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate.

The combined organic layer was washed with 0.5M aqueous sodium hydroxide solution, filtered through

Celite (trade name), washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluate; ethyl acetate/hexane-3/17-2/1) and crystallized from ethyl acetate-isopropyl ether to give the title compound (821 mg, 64 vol). "H-NMR (300 MHz, SOSI") 6: 1.42 (ZN, t, 9U-7.2 Hu), 1.84-2.19 (AN, m), 3.74 (ZN, s) , 3.76-3.85 (1H, m), 3.89-3.98 (1H, m), 4.22-4.49 (5H, m), 7.27 (1H, ddd, 9U- 8.0, 7.1, 1.0 Hz), 7.39 (1TN, d, U-8.1 Hz), 7.58 (1Н, ddd, U-8.6, 7.1, 1, 4 Hz), 7.81-7.86 (1H, m).

Auxiliary Example 90

Preparation of 3-(2-ethoxyethoxy)-5-methyl-4-oxo-4,5-dihydrothieno|3,2-c)quinoline-2-carboxylate

SO, Hey

WITH

X p

M'To OEI

Me

To a suspension of the compound of Auxiliary Example 82 (1.00 g, 3.30 mmol) in DMF (20 ml) was added OVIU (1.48 ml, 9.90 mmol) and to the resulting solution was added 1-bromo-2-ethoxyethane (1 .12 ml, 9.93 mmol).

The resulting mixture was stirred at 60 C for 24 hours. Ethyl acetate and water were added to the reaction mixture, the organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with 0.5M aqueous sodium hydroxide solution, filtered through Celite (trade name), then washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluate; ethyl acetate/hexane-1/4-1/1) and crystallized from ethyl acetate-hexane to give the title compound (986 mg, 80 95). "H-NMR (300 MHz, SOSI") 6: 1.19 (ZN, t, 9U-7.0 Hz), 1.43 (ZN, t, U-7.1 Hz), 3.59 (2Н , k, U-7.0 Hz), 3.74 (ZH, s), 3.93 (2H, t, U-5.0 Hz), 4.40 (2H, k, 9-71 Gu), 4.46 (2H, t, 9U-5.0 Hz), 7.26-7.31 (1H, m), 7.40 (1H, d,

U-8.5 Hz), 7.58 (1H, ddd, 9U-8.5, 7.2, 1.4 Hz), 7.84 (1H, dd, U-8.0, 1.4 Hz ).

Auxiliary Example 91

Preparation of 3-(benzyloxy)-5-methyl-4-oxo-4,5-dihydrothieno|3,2-s|quinoline-2-carboxylic acid

SLEEP

WITH

X so o

M (c)

Me

To a solution of the compound of Auxiliary Example 85 (867 mg, 2.20 mmol) in THF (7 mL) and ethanol (7 mL) was added 5M aqueous sodium hydroxide solution (0.88 mL, 4.4 mmol). The resulting mixture was stirred at room temperature for 3 hours. 1M hydrochloric acid (5.0 mL) was added to the reaction mixture and the precipitated solid was collected by filtration, washed with water and air dried to give the title compound (665 mg, 83 95). "H-NMR (300 MHz, DMSO-α) 6: 3.69 (ZH, s), 5.22 (2H, s), 7.30-7.41 (4H, m), 7.57-7 .72 (AN, m), 7.98 (IN, d, U-8.1 Gu), 13.31 (IN, w s).

Auxiliary Example 92

Preparation of 3-butoxy-5-methyl-4-oxo-4,5-dihydrothieno|3,2-c|quinoline-2-carboxylic acid

SLEEP

WITH

X sb d, o shoi

Me

To a solution of the compound of Auxiliary Example 86 (923 mg, 2.57 mmol) in THF (7 mL) and ethanol (7 mL) was added 5M aqueous sodium hydroxide solution (1.0 mL, 5.0 mmol). The resulting mixture was stirred at room temperature for 3 hours. 1M hydrochloric acid (6.0 mL) was added to the reaction mixture and the precipitated solid was collected by filtration, washed with water and air dried to give the title compound (872 mg, quantitative yield). "H-NMR (300 MHz, DMSO-av) 6: 0.94 (ZH, t, 9U-7.5 Hz), 1.41-1.55 (2H, m), 1.71-1.82 (2H, m), 3.65 (ZH, s), 4.16 (2H, t, U-6.6 Hu), 7.32 (1H, t, U-7.2 Hu), 7.54 -7.70 (2H, m), 7.91-7.98 (1H, m), 13.21 (IN, w s).

Auxiliary Example 93

Preparation of 5-methyl-4-oxo-3-(pyridin-4-ylmethoxy)-4,5-dihydrothieno|3,2-c|quinoline-2-carboxylic acid

SLEEP

WITH

X Sat because A

Me

To a suspension of the compound of Auxiliary Example 87 (723 mg, 1.83 mmol) in THF (6 mL) and ethanol (6 mL) was added 5M aqueous sodium hydroxide solution (0.74 mL, 3.7 mmol). The resulting mixture was stirred at room temperature for 4 hours. 1M hydrochloric acid (3.7 ml) was added to the reaction mixture and the mixture was diluted with water. The resulting solid was collected by filtration, washed with water and air dried to give the title compound (424 mg, 63 95). "H-NMR (300 MHz, DMSO-α) 5: 3.67 (ZH, s), 5.28 (2H, s), 7.32-7.38 (1H, m), 7.59-7 .72 (AN, m), 7.98 (IN, dd, 9U-7.8, 1.2 Hz), 8.59 (2Н, dd, 954.5, 1.5 Hz).

Auxiliary Example 94

Preparation of / 5-methyl-3-(2-morpholin-4-ylethoxy)-4-oxo-4,5-dihydrothieno|3,2-c|quinoline-2-carboxylic acid

SLEEP

WITH

Their Sat

Mo

Me with (6)

To a suspension of the compound of Auxiliary Example 88 (832 mg, 2.00 mmol) in THF (7 mL) and ethanol (7 mL) was added 5M aqueous sodium hydroxide solution (0.80 mL, 4.0 mmol). The resulting mixture was stirred at room temperature for 4 hours. 1M hydrochloric acid (4.0 ml) was added to the reaction mixture and the mixture was diluted with water and concentrated under reduced pressure. Methanol was added to the residue and the mixture was concentrated under reduced pressure and crystallized from water-methanol to give the title compound (477 mg, 61 95). "H-NMR (300 MHz, DMSO-av) 6: 3.00-3.20 (6H, m), 3.67 (ZH, s), 3.84 (4H, w t, 9-44 Hu) , 4.53 (2H, pc, 9-5.0 Hz), 7.31 (1H, ddd, U-8.0, 6.3, 1.8 Hz), 7.55-7.67 (2H , m), 7.88-7.91 (1H, m).

Auxiliary Example 95

Preparation of 5-methyl-4-oxo-3-(tetrahydrofuran-2-ylmethoxy)-4,5-dihydrothieno|3,2-c|quinoline-2-carboxylic acid

СО,Н and с (c) -

M (c)

Me

To a suspension of the compound of Auxiliary Example 89 (728 mg, 1.88 mmol) in THF (6 mL) and ethanol (6 mL) was added 5M aqueous sodium hydroxide solution (0.76 mL, 3.8 mmol). The resulting mixture was stirred at room temperature for 4 hours. 1M hydrochloric acid (3.8 ml) was added to the reaction mixture and the mixture was diluted with water, and the mixture was extracted with chloroform three times. The combined organic layer was washed with aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting solid was washed with isopropyl ether to give the title compound (659 mg, 97 Vol). "H-NMR (300 MHz, DMSO-dv) 6: 1.73-2.04 (AN, m), 3.56-3.78 (2H, m), 3.65 (ZH, s), 4 .02-4.10 (1H, m), 4.19-4.30 (2H, m), 7.29-7.37 (1H, m), 7.57-7.71 (2H, m) , 7.92-7.99 (1H, m), 13.20 (IN, w s).

Auxiliary Example 96

Preparation of 3-(2-ethoxyethoxy)-5-methyl-4-oxo-4,5-dihydrothieno|3,2-c)quinoline-2-carboxylic acid

SLEEP

WITH

X p

M'o OEi

Me

To a suspension of the compound of Auxiliary Example 90 (826 mg, 2.20 mmol) in THF (7 mL) and ethanol (7 mL) was added 5M aqueous sodium hydroxide solution (0.88 mL, 4.4 mmol). The resulting mixture was stirred at room temperature for 2.5 hours, 5M aqueous sodium hydroxide solution (4.4 ml, 22 mmol) was added and the mixture was stirred at 50 "C for 3.5 hours. The reaction mixture was acidified with 1M hydrochloric acid and diluted with water. and the precipitated solid was collected by filtration, washed with water and air dried to give the title compound (719 mg, 94 b). "H-NMR (300 MHz, DMSO-α) 6: 1.03 (ZH, t , U-6.9 Hz), 3.44 (2H, k, U-6.9 Hz), 3.66 (ZH, s), 3.75 (2H, t, 925.0 Hz), 4, 33 (2H, t, 9U-5.0 Gu), 7.33 (1H, t, U-7.4 Hz), 7.58-7.71 (2H, m), 7.96 (1H, d , 9-81 Gu), 13.21 (IN, w s).

Auxiliary Example 97

Preparation of 1-butyl-2H-3,1-benzoxazine-2,4(1H)-dione from soy

I

Me

To a solution of isoic anhydride (8.16 g, 50.0 mmol) in DMF (100 mL) was added sodium hydride (66 95 in oil, 2.00 g, 55 mmol) while cooling on ice, and the mixture was stirred at the same temperature for 10 minutes. 1-iodobutane (8.5 mL, 75 mmol) was added to the resulting mixture and the mixture was stirred at room temperature for 64 hours. Ice water was added to the reaction mixture and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed twice with water and concentrated under reduced pressure to give the title compound (10.5 g), which was used for the next reaction without purification. "H-NMR (300 MHz, SOS") 6: 1.01 (ZH, t, U-7.4 Hz), 1.48 (2H, sext., uU-7.4 Hz), 1.69- 1.81 (2H, m), 4.02-4.10 (2H, m), 7.17 (1H, d, U-8.6 Hz), 7.25-7.32 (1H, m) , 7.75 (1H, ddd, 9-8.6, 7.4, 1.7 Hz), 8.16 (1H, ddd, 97.8, 1.7 Gu).

Auxiliary Example 98

Preparation of ethyl 1-butyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate

Me

To a solution of diethylmalonate (12.0 g, 74.9 mmol) in DMF (70 mL) was added sodium hydride (66 95 in oil, 2.00 g, 55 mmol) while cooling on ice, and the mixture was stirred at the same temperature for 10 minutes A solution of the compound of Auxiliary Example 97 (10.5 g) in DMF (20 ml) was added dropwise to the resulting mixture, and the mixture was stirred at 120 °C for 2 hours. The reaction mixture was concentrated under reduced pressure, ice water was added to the residue, and the resulting aqueous layer was washed The aqueous layer was slightly acidified with 5M hydrochloric acid (12 ml)

under cooling on ice and extracted with ethyl acetate. The combined organic layer was washed with water and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluate; ethyl acetate/hexane-1/9-1/2) to give the title compound (9.96 g, 69 95, 2 steps) as a solid. "H-NMR (300 MHz, SOS") 6: 0.99 (ZN, t, 9U-7.4 Hu), 1.482 (2H, sext, uU-7.4 Hz), 1.485 (ZN, t, 9U -7.1 Gu), 1.64-1.76 (2H, m), 4.17-4.26 (2H, m), 4.50 (2H, k, 957.1 Hz), 7.20 -7.26 (1H, m), 7.29 (1H, d, U-8.4 Hz), 7.66 (IN, ddd, 9-8.6, 7.4, 1.6 Hz), 8.18 (1H, dd, U-8.3, 1.6 Gu), 14.20 (1H, s).

Auxiliary Example 99

Production of ethyl 1-butyl-4-chloro-2-oxo-1,2-dihydroquinoline-3-carboxylate

SI

I. shk c) what

A mixture of the compound of Auxiliary Example 98 (9.73 g, 33.6 mmol) and phosphorus oxychloride (4.7 ml, 50 mmol) was stirred at 110 C for 30 minutes. The reaction mixture was concentrated under reduced pressure and ice water and ethyl acetate were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, saturated sodium bicarbonate solution and water (twice), and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (eluate; ethyl acetate/hexane-1/9-1/3) and the fractions containing the target product were combined and washed with 1M sodium hydroxide solution and water (twice). The insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The residue was crystallized from ethyl acetate-diisopropyl ether to give the title compound (6.07 g, 59 b). "H-NMR (300 MHz, SOSIz) 5: 1.00 (ZN, t, 9U-7.4 Hu), 1.42 (ZN, t, 9-7.2 Hz), 1.42-1, 56 (2H, m), 1.67-1.79 (2H, m), 4.23-4.31 (2H, m), 4.47 (2H, k, U-7.2 Hz), 7 ,33 (1H, ddd, 9-81, 7.2, 0.9 Gu), 7.37-7.41 (1H, m), 7.66 (IN, ddd, 9-8.7, 7, 2, 1.4 Hz), 8.07 (1H, dd, U-8.1, 1.4 Hz).

Auxiliary Example 100

Production of ethyl 5-butyl-3-hydroxy-4-oxo-4,5-dihydrothieno|3,2-c)quinoline-2-carboxylate

SO, EI

WITH

A solution (16.0 g, 47 mmol) of sodium ethoxide in ethanol was diluted with ethanol (45 ml), ethyl thioglycolate (6.2 ml, 55 mmol) was added to the resulting solution, and the mixture was stirred at room temperature for 10 minutes To this mixture was added the compound of Auxiliary Example 99 (7.21 g, 23.4 mmol) and the mixture was stirred at room temperature for 5 hours. The reaction mixture was neutralized with ice water and 2M hydrochloric acid (25 mL) while cooling on ice, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed twice with water and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-diisopropyl ether to give the title compound (6.44 g, 80 95). "H-NMR (300 MHz, SOSIz) 5: 1.02 (ZN, t, 9-74 Hu), 1.42 (ZN, t, 9-7.2 Hu), 1.44-1.58 ( 2H, m), 1.71-1.83 (2H, m), 4.29-4.36 (2H, m), 4.41 (2H, k, 9U-7.2 Hz), 7.32 (1H, ddd, uU-8.0, 7.2, 0.9 Hz), 7.43-7.48 (1H, m), 7.61 (IN, ddd, 9-8.6, 7, 3, 1.6 Hz), 7.81-7.86 (1H, m), 10.81 (1H, s).

Helping Example 101

Production of ethyl 5-butyl-3-methoxy-4-oxo-4,5-dihydrothieno-3,2-c|quinoline-2-carboxylate

SO, EI

WITH

X g

Me

To a suspension of the compound of Auxiliary Example 100 (3.11 g, 9.00 mmol) in DMF (30 mL) was added OVO (1.62 mL, 10.8 mmol) and to the resulting solution was added iodomethane (1.12 mL, 18, 0 mmol). The resulting mixture was stirred at room temperature for 14 hours, water was added and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with water and 0.5M aqueous sodium hydroxide solution, filtered through Celite (trade name), then washed twice with water and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluate; ethyl acetate/hexane-1/4-1/1) and recrystallized from ethyl acetate-hexane to give the title compound (1.03 g, 32 Vol). "H-NMR (300 MHz, SOS") 6: 1.01 (ZH, t, U-7.4 Hu), 1.40-1.60 (2H, m), 1.42 (ZH, t, 9U-7.2 Hz), 1.69-1.81 (2H, m), 4.14 (ZH, s), 4.28-4.36 (2H, m), 4.40 (2H, k , 9U-7.2 Gu), 7.22-7.29 (1H, m), 7.39 (1H, d, U-8.5 Hz), 7.57 (IN, ddd, 3-8, 5, 7.1, 1.4 Hz), 7.84 (1H, dd, U-8.0, 1.4 Hz).

Auxiliary Example 102

Preparation of ethyl 5-butyl-3-(2-ethoxyethoxy)-4-oxo-4-5-dihydrothienoic acid, 3,2-c, quinoline-2-carboxylate

SO, EI

WITH

H ov 7 o); OEI

Me

To a suspension of the compound of Auxiliary Example 100 (1.14 g, 3.30 mmol) in DMF (20 mL) was added OVI (1.48 mL, 9.90 mmol) and to the resulting solution was added 1-bromo-2-ethoxyethane (1 .12 ml, 9.93 mmol).

The resulting mixture was stirred at 60 "C for 30 hours, and ethyl acetate and water were added to the reaction mixture. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with 0.5 M aqueous sodium hydroxide solution and water, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluate; ethyl acetate/hexane-1/4-1/2) to give the title compound (1.28 g, 93 95) as a solid. "H-NMR (300 MHz , SOS") 6: 1.01 (ZN, t, U-7.4 Hz), 1.18 (ZN, t, 9U-7.0 Hz), 1.42 (ZN, t, 9U-7, 2 Hz), 1.43-1.57 (2H, m), 1.65-1.79 (2H, m), 3.58 (2H, k, 9-7.0 Hz), 3.92 ( 2H, dd, uU-5.6, 4.7 Hz), 4.30 (2H, pcs, U-7.8 Gu), 4.39 (2H, k, 9-7.2 Hz), 4, 47 (2H, t, 95.1 Pu, 7.21-7.28 (1H, m), 7.37 (1H, d, U-8.5 Hz), 7.56 (1H, ddd, 98, 5, 7.1, 1.4 Gu), 7.83 (1H, dd, 9U-8.1, 1.4 Hz).

Auxiliary Example 103

Preparation of 5-butyl-3-methoxy-4-oxo-4,5-dihydrothieno|3,2-c)quinoline-2-carboxylic acid

SLEEP

WITH

Their

I. Shk o) what

To a suspension of the compound of Auxiliary Example 101 (1.81 g, 5.04 mmol) in THF (15 mL) and ethanol (15 mL) was added 5M aqueous sodium hydroxide solution (2.0 mL, 10 mmol). The resulting mixture was stirred at room temperature for 1.5 hours. The reaction mixture was cooled on ice, 1M hydrochloric acid (15 mL) and ethyl acetate were added, and the precipitated solid was collected by filtration and washed with water and ethyl acetate to give a solid. The filtrate was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and concentrated under reduced pressure. The residue and the previously obtained solid were combined and the mixture was recrystallized from methanol-diisopropyl ether to give the title compound (1.43 g, 86 Vol). "H-NMR (300 MHz, DMSO-av) 6: 0.95 (ZH, t, 9-7.3 Hu), 1.43 (2H, sext, U-7.3 Hz), 1.56- 1.68 (2H, m), 3.95 (ZH, s), 4.29 (2H, t, 9-7.5 Hz), 7.29-7.36 (1H, m), 7.60 -7.71 (2H, m), 7.95-8.00 (1H, m).

Auxiliary Example 104

Preparation of 5-butyl-3-(2-ethoxyethoxy)-4-oxo-4,5-dihydrothieno3,2-c|quinoline-2-carboxylic acid

SLEEP

WITH

H ov 7 o); OEI

Me

To a solution of the compound of Auxiliary Example 102 (1.16 g, 2.78 mmol) in THF (9 mL) and ethanol (9 mL) was added 5M aqueous sodium hydroxide solution (1.12 mL, 5.6 mmol). The resulting mixture was stirred at room temperature for 2.5 hours, 5M aqueous sodium hydroxide solution (4.48 mL, 22 mmol) was added, and the mixture was stirred at 50 "C for 3 hours. The reaction mixture was acidified with 1M hydrochloric acid and extracted twice with chloroform. The combined organic layer was washed with water and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-diisopropyl ether to give the title compound (965 mg, 89 b). "H-NMR (300 MHz, DMSO-α) 6: 0.95 (ZN, t, 9-7.3 Gu), 1.02 (ZN, t, U-7.0 Hz), 1.43 (2H, sext, U-7.3

Hz), 1.56-1.68 (2H, m), 3.43 (2H, k, 9U-7.0 Hz), 3.74 (2H, t, 9U-5.0 Gu), 4, 24-4.40 (2H, m), 4.30 (2H, t, U-5.0

Hz), 7.32 (IN, t, 9-7.4 Hz), 7.59-7.71 (2H, m), 7.97 (1TN, d, 9U-7.5 Hz), 13, 20 (IN, w s).

Auxiliary Example 105

Preparation of //3-hydroxy-5-(4-methoxybenzyl)-1-methyl-4-oxo-4,5-dihydro-1H-pyrrolo|3,2-c|quinoline-2-carboxylate

Me SO, Hey

M

H

I. Shk 6). Ome

According to a method similar to the method given in Auxiliary Example 25, ethyl 4-(2-ethoxy-2-oxoethyl)(methyl)amino|-1-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-Z3 -carboxylate (14.7 g, 63 Ob) was obtained as a white powder from the compound of Auxiliary Example 10 (19.2 g, 51.6 mmol).

By a procedure similar to that given in Auxiliary Example 26, the title compound (10.35 g, 49 95) was obtained as a white solid from ethyl 4-((2-ethoxy-2-oxoethyl)(methyl)amino| -1-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-3-carboxylate (14.73 g). "H-NMR (300 MHz, SOCI3) 6: 1.33 (ZH, t, 9 -7.1 Gu), 3.69 (ZN, s), 4.27 (ZN, s), 4.34 (2H, k, 9-71 Hu), 5.47 (2H, s), 6, 86 (2H, d, 9-8.7 Hz), 7.16 (2H, d, U-8.7 Hz), 7.27-7.30 (1H, m), 7.48 (2H, d , 9U-3.3 Hu), 8.32 (IN, d, U-8.1 Hu), 9.10 (1H, s).

Auxiliary Example 106

Preparation of 3-methoxy-5-(4-methoxybenzyl)-1-methyl-4-oxo-4,5-dihydro-1H-pyrrolo|3,2-c|quinoline-2-carboxylate

Me SO, Hey

M

H

I. Shk 6). Ome

By a procedure similar to that given in Auxiliary Example 6, the title compound (6.51 g, 6195) was obtained as a pale yellow solid from the compound

Auxiliary Example 105 (10.4 g, 25.5 mmol). "H-NMR (300 MHz, DMSO-av) 5: 1.35 (ZN, t, 9-7.1 Hu), 3.69 (ZN, s), 3.94 (ZN, s), 4, 26 (ZN, s), 4.34 (2H,

Kk, 9-7.1 Gu), 5.51 (2H, w s), 6.86 (2H, d, 9U-8.7 Hz), 7.15 (1H, d, U-8.4 Hz ), 7.25-7.31 (1H, m), 7.47 (2H, d, 3-3.6 Hz), 8.34 (1H, d, 9-81 Hz).

Auxiliary Example 107

Preparation of 3-methoxy-5-(4-methoxybenzyl)-1-methyl-4-oxo-4,5-dihydro-1H-pyrrolo|3,2-c|quinoline-2-carboxylic acid

M

H

I. M is) and OMe

By a procedure similar to that given in Auxiliary Example 28, the title compound (5.67 g, 96 96) was obtained as a pale yellow solid from the compound

Auxiliary Example 106 (6.50 g, 15.5 mmol). "H-NMR (300 MHz, DMSO-α) 6: 3.70 (ZH, s), 3.94 (ZH, s), 4.28 (ZH, s), 5.51 (2H, w s) , 6.86 (2H, d,

U-8.7 Hz, 7.15 (1H, d, U-8.4 Hz), 7.25-7.30 (1H, m), 7.46 (2H, d, 9U-3.9 Gu ), 8.34 (1TN, d, U-8.4 Gu), 12.90 (IN, w s).

Auxiliary Example 110

Preparation of ethyl 6-fluoro-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate one se

Mo

N

By a procedure similar to that given in Auxiliary Example 1, the title compound (8.60 g, 56 95) was obtained as a pale yellow solid from ethyl 2-amino-5-fluorobenzoate (10.3 g, 61.0 mmol), diethylmalonate (9.2 ml, 61.0 mmol), 20 95 solution (21.0 g, 61.0 mmol) of sodium ethoxide in ethanol and ethanol (70 ml). "H-NMR (300 MHz, SOSIz) 5: 1.52 (ZH, t, 9-7.2 Hz), 4.54 (2H, k, 9-71 Hz), 7.20-7.29 ( 1H, m), 7.31-7.42 (IN, m), 7.75 (1H, dd, U-8.6, 2.7 Gu), 11.02 (IN, w s), 14, 31 (1H, p.).

Auxiliary Example 111

Production of ethyl 2,4-dichloro-b6-fluoroquinoline-3-carboxylate

(and -

MY

By a method similar to that given in Auxiliary Example 2, the title compound (2.2 g, 96 95) was obtained as a white solid from the compound of Auxiliary

Example 110 (2.0 g, 7.8 mmol) and phosphorus oxychloride (9.0 ml). "H-NMR (300 MHz, SOSIz) 6: 1.46 (ZH, t, 9U-7.1 Hz), 4.54 (2H, k, 9-7.2 Hu), 7.54-7, 68 (1H, m), 7.86 (1H, dd, 4-9.1, 2.8 Hz), 8.07 (1H, dd, 99.2, 5.2 Hz).

Auxiliary Example 112

Preparation of ethyl 4-chloro-6-fluoro-2-oxo-1,2-dihydroquinoline-3-carboxylate (Fi

So she;

N

By a method similar to that given in Auxiliary Example 3, the title compound (1.6 g, 79 95) was obtained as a white solid from the compound of Auxiliary

Example 111 (2.2 g, 7.5 mmol), sodium acetate (615 mg, 7.5 mmol) and acetic acid (20 ml). "H-NMR (300 MHz, SOSIv) 5: 1.40-1.51 (3H, m), 4.46-4.57 (2H, m), 7.36-7.46 (2H, m) , 7.69 (1H, dd, 9-91, 1.9 Gu), 12.36 (IN, w s).

Auxiliary Example 113

Preparation of ethyl 4-chloro-6-fluoro-2-oxo-1-(2-oxo-2-phenylethyl)-1,2-dihydroquinoline-3-carboxylate

SI se

I. M is) x

By a procedure similar to that given in Auxiliary Example 4, the title compound (1.3 g, 57 90) was obtained as a pale yellow solid from the compound

Auxiliary Example 112 (1.6 g, 5.9 mmol), sodium hydride (60 95 in oil, 248 mg, 6.2 mmol), phenacyl bromide (1.3 g, 6.5 mmol), and DMF (20 mL) . "H-NMR (300 MHz, SOSIZ3) 6: 1.42 (ZH, t, 9-71 Hz), 4.47 (2H, k, 97.1 Hu), 5.79 (2H, s), 7 .00 (1H, dd, 9U-9.3, 4.2 Hz), 7.27-7.38 (1H, m), 7.49-7.61 (2H, m), 7.63-7 .73 (1TN, m), 7.80 (1Н, dd, 9U-9.1, 2.68 Gu), 8.02-8.12 (2Н, m).

Auxiliary Example 114

Production of ethyl 8-fluoro-3-hydroxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno|3,2-c)quinoline-2-carboxylate

CO,

WITH

And She) I

By a method similar to that given in Auxiliary Example 5, the title compound (1.3 g, 94 95) was obtained as a yellow solid from the compound of Auxiliary

Example 113 (1.3 g, 3.3 mmol), 2095 solution (2.3 g, 6.7 mmol) of sodium ethoxide in ethanol, ethyl thioglycolate (0.97 g, 8.0 mmol) and ethanol (14 ml) . "H-NMR (300 MHz, DMSO-α) 6: 1.32 (ZH, t, 9-7.1 Hz), 4.32 (2H, k, 9-7.2 Hz), 6.02 ( 2H, c), 7.47-7.58 (IN, m), 7.59-7.70 (ZH, m), 7.72-7.82 (1H, m), 8.00 (1H, dd, 9U-8.7, 2.8 Gu), 8.11-8.21 (2H, m), 10.52 (IN, w s).

Auxiliary Example 115

Production of ethyl 8-fluoro-33-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno|3,2-c)quinoline-2-carboxylate

SOY

WITH

H

Ehhh OMe

I MF) x

By a procedure similar to that given in Supplementary Example 6, the title compound (880 mg, 6595) was obtained as a yellow solid from the compound

Auxiliary Example 114 (1.3 g, 3.1 mmol), iodomethane (0.31 mL, 5.0 mmol), OVI (0.75 mL, 5.0 mmol), and DMF (40 mL). "H-NMR (300 MHz, SOSIz) 6: 1.43 (ZH, t, 97.5 Hu), 4.12 (ZH, s), 4.42 (2H, k, 9-7.2 Hz) , 5.84 (2H, s), 6.98 (1H, dd, U-9.3, 4.2 Hz), 7.16-7.25 (1H, m), 7.49-7.60 (ЗН, m), 7.64-7.72 (1Н, m), 8.03-8.15 (2Н, m).

Auxiliary Example 116

Preparation of 8-fluoro-3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno|3,2-c|quinoline-2-carboxylic acid

SLEEP

WITH

Me)

By a procedure similar to that given in Auxiliary Example 7, the title compound (602 mg, 73 95) was obtained as a pale brown solid from the compound

Auxiliary Example 115 (880 mg, 2.0 mmol), 8M aqueous solution of sodium hydroxide (5.7 ml), ethanol (32 ml) and THF (9.1 ml). "H-NMR (300 MHz, DMSO-α) 5: 3.92 (ZH, s), 5.98 (2H, s), 7.39-7.60 (2H, m), 7.60-7 .69 (2H, m), 7.72-7.81 (IN, m), 7.91-8.01 (1H, m), 8.12-8.23 (2H, m).

Auxiliary Example 117

Preparation of ethyl 8-fluoro-3-hydroxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo!13,2-c|quinoline-2 -carboxylate

Soybeans

M

Me)

I

By a procedure similar to that given in Auxiliary Example 25, the title compound (4.1 g, 83,906) was obtained as a pale brown solid from the compound

Auxiliary Example 113 (4.6 g, 12 mmol), sarcosine ethyl ester hydrochloride (4.5 g, 30 mmol), triethylamine (6.0 ml, 43 mmol), ethanol (35 ml), 20 95 solution (3, 4 g, 9.9 mmol) of sodium ethoxide in ethanol and ethanol (35 ml). "H-NMR (300 MHz, DMSO-av) 5: 1.33 (ZH, t, U-8.9 Hz), 4.26-4.42 (5H, m), 5.94 (2H, s ), 7.33-7.50 (2Н, m), 7.58-7.69 (2Н, m), 7.71-7.80 (1Н, m), 8.03-8.23 (ЗН , m), 9.01 (1H, w s).

Auxiliary Example 118

Preparation of ethyl 8-fluoro-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo|3,2-c)quinoline-2 -carboxylate

Soybeans

M

Mo x

A solution of the compound of Auxiliary Example 117 (3.4 g, 8.0 mmol), dimethylsulfuric acid (1.1 mL, 12 mmol) and VI (2.4 mL, 16 mmol) in DMF (100 mL) was stirred at room temperature for 2.5 hours. Dimethylsulfuric acid (1.1 mL, 12 mmol) and OVI (2.4 mL, 16 mmol) were added to the reaction mixture, and the mixture was stirred at room temperature for 1 day. Dimethylsulfuric acid (0.75 mL, 8.0 mmol) and OVI (1.8 mL, 11 mmol) were then added, and the mixture was stirred at room temperature for 21 h and diluted with water, and the precipitated solid was collected by filtration. The resulting solid was washed with water and dried under reduced pressure to give the title compound (2.8 g, 80 95) as a white solid. "H-NMR (300 MHz, DMSO-av) 6: 1.35 (ZH, t, 9U-7.1 Hz), 3.88 (ZH, s), 4.21-4.42 (5H, m ), 5.96 (2H, s), 7.28-7.51 (2H, m), 7.55-7.69 (2H, m), 7.71-7.81 (1H, m), 7.98-8.39 (ZN, m).

Auxiliary Example 119

Preparation of 8-fluoro-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo|3,2- sequinoline-2-carboxylic acid

Me SO, Nn "M

Their

E with OMe

M o h

By a procedure similar to that given in Auxiliary Example 7, the title compound (2.4 g, 9095) was obtained as a pale yellow solid from the compound

Auxiliary Example 118 (2.8 g, 6.4 mmol). "H-NMR (300 MHz, DMSO-α) 6: 3.85 (ZH, s), 4.30 (ZH, s), 5.95 (2H, s), 7.19-7.49 (2H , m), 7.53-7.69 (2Н, m), 7.70-7.82 (1Н, m), 7.97-8.26 (ЗН, m).

Auxiliary Example 120

Preparation of /1-ethyl-3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo|3,2-c)quinoline-2-carboxylic acid

IF)

E ON

M

I. Me; h

A solution of the compound of Auxiliary Example 4 (1.0 g, 2.7 mmol), M-ethylglycine ethyl ester hydrochloride (499 mg, 3.0 mmol) and triethylamine (3.8 ml, 27 mmol) in 1-butanol (10 ml ) was heated at reflux for 6 hours. M-ethylglycine ethyl ester hydrochloride (499 mg, 3.0 mmol) was added and the mixture was heated at reflux for 17 hours. M-ethylglycine ethyl ester hydrochloride (499 mg, 3.0 mmol) and triethylamine (0.41 mL, 3.0 mmol) were added, and the mixture was heated at reflux for 6 hours, and M-ethyl ester hydrochloride was added -ethylglycine (499 mg, 3.0 mmol) and triethylamine (0.41 mL, 3.0 mmol), and the mixture was heated at reflux for 6 hours. Water was added to the reaction mixture and the precipitated solid was collected by filtration. The obtained solid was washed with water and dried under reduced pressure. A mixture of the obtained solid, 20 95 solution (777 mg, 2.3 mmol) of sodium ethoxide in ethanol and ethanol (150 ml) was stirred at room temperature for 5 hours. 20 95 solution (777 mg, 2.3 mmol) of sodium ethoxide in ethanol was added and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water, neutralized with 5M hydrochloric acid, and the mixture was stirred for 30 minutes. The resulting solid was collected by filtration, washed with water, dried under reduced pressure and recrystallized from DMF-diethyl ether. Dimethyl sulfuric acid (0.092 mL, 0.97 mmol) was added to a solution of the obtained solid and OVI (0.19 mL, 1.3 mmol) in DMF (8.0 mL) while cooling on ice, and the mixture was stirred at room temperature for 14 hours

OVO (0.19 mL, 1.3 mmol) and dimethylsulfuric acid (0.092 mL, 0.97 mmol) were then added while cooling on ice, and the mixture was stirred at room temperature for 4 hours and diluted with water. The resulting solid was collected by filtration, the resulting solid was washed with water and dried under reduced pressure. A mixture of a solution of the obtained solid and an 8M solution of sodium hydroxide (1.4 ml) in THF (2.3 ml)-ethanol (8.0 ml) was stirred at room temperature for 15 hours. 8M sodium hydroxide solution (0.70 ml) was added and the mixture was stirred at room temperature for 3.5 hours. Then 8M sodium hydroxide solution (0.14 ml) was added and the mixture was stirred at room temperature for 3 hours. The reaction mixture was neutralized with 1M hydrochloric acid and concentrated under reduced pressure, and the precipitated solid was collected by filtration. The resulting solid was washed with water and dried under reduced pressure to give the title compound (180 mg, 16 95) as a white solid. "H-NMR (300 MHz, DMSO-av) 5: 1.51 (ZH, t, U-6.5 Hz), 3.86 (ZH, s), 4.85 (2H, k, 9-7 ,0 Hz), 5.97 (2H, s), 7.217-7.43 (2H, m), 7.44-7.54 (1H, m), 7.58-7.69 (2H, m) , 7.71-7.83 (1H, m), 8.01-8.45 (ZH, m), 12.89 (1H, w s).

Auxiliary Example 121

Preparation of tert-butyl (1-benzylazepan-4-yl/ucarbamate

"Vp in,

Vos-M

N

Di-tert-butyl dicarbonate (591 mg, 2.7 mmol) while cooling on ice and the mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate. The extracts were combined, washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure.

The residue was purified by chromatography on amino silica gel (eluate: ethyl acetate/hexane-10/90-100/0) to give the title compound (447 mg, quantity) as a colorless oil. "H-NMR (300 MHz, SOCI3) 6: 1.45 (9H, s), 1.53-1.77 (5H, m), 1.78-1.93 (1H, m), 2.37 -2.58 (2H, m), 2.61- 2.83 (2H, m), 3.61 (2H, s), 3.73-4.00 (1H, m), 4.92-5 .27 (1H, m), 7.07-7.44 (5H, m).

Auxiliary Example 122

Preparation of tert-butyl azepan-4-ylcarbamate nH y,

Vos-M

N

A solution of the compound of Auxiliary Example 121 (447 mg, 1.5 mmol) and palladium on carbon (65 mg) in ethanol (10 mL) was stirred at room temperature for 4.5 hours under a hydrogen atmosphere.

Palladium on charcoal was filtered off and the filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (10 mL), palladium on carbon (120 mg) was added, and the mixture was stirred at room temperature for 4.5 hours under a hydrogen atmosphere. The palladium on charcoal was filtered off and the filtrate was concentrated under reduced pressure to give the title compound (315 mg, quant.) as a colorless oil. "H-NMR (300 MHz, SOSI") 5: 1.34-1.76 (1H, m), 1.78-2.07 (2H, m), 2.39-2.70 (1H, m ), 2.71-3.04 (AN, m),

C.66-3.94 (1H, m), 4.60-5.01 (1H, m).

Auxiliary Example 123

Preparation of 2-14-tert-butoxycarbonyl)amino|azepan-1-yl)y-2-oxoethyl acetate uh g

Vos-M

N

By a procedure similar to that of Example 544, the title compound (220 mg, 96 95) was obtained as a white solid from the compound of Auxiliary Example 122 (157 mg, 0.73 mmol). "H-NMR (300 MHz, SOS") 6: 1.37-1.55 (11H, m), 1.61-2.00 (AN, m), 2.07-2.23 (AN, m ), 3.21-3.77 (4H, m), 4.35-4.59 (1H, m), 4.59-4.81 (2H, m).

Auxiliary Example 124

Production of methyl 2-aminopyridine-3-carboxylate and CO,Me

Fi

M MN,

To a solution of 2-aminopyridine-3-carboxylic acid (4.3 g, 31 mmol) in methanol (62 mL) was added dropwise sulfuric acid (31 mL) while cooling on ice, and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was stirred at 70 "C for 15 hours and neutralized with sodium bicarbonate while cooling on ice. The reaction mixture was extracted twice with ethyl acetate and the extracts were combined and washed with saturated saline.

The extract was dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (4.3 g, 90 95) as a white solid. "H-NMR (300 MHz, SOSI") 6: 3.89 (ZH, s), 6.38 (2H, w s), 6.63 (1H, dd, 9-7.8, 4.8 Hz ), 8.13 (1H, dd, 9-7.7, 1.9 Gu), 8.22 (1H, dd, 9U-4.7, 1.9 Hz).

Auxiliary Example 125

Preparation of ethyl 4-hydroxy-2-oxo-1,2-dihydro-1,85-naphthyridine-3-carboxylate and. We M d)

N

By a procedure similar to that given in Auxiliary Example 1, the title compound (2.6 g, 53 95) was obtained as a pale purple solid from the compound

Auxiliary Example 124 (3.1 g, 21 mmol). "H-NMR (300 MHz, DMSO-av) 5: 1.30 (ZN, t, 9U-7.1 Hu), 4.32 (2H, k, 9-71 Hu), 7.27 (IN, dd, 9-7,9, 4,7

Hz), 8.22-8.38 (1H, m), 8.60 (1H, dd, 9U-4.6, 1.8 Gu), 11.86 (1H, s), 13.29 (IN , w c).

Auxiliary Example 126

Preparation of ethyl 2,4-dichloro-1,8-naphthyridine-3-carboxylate

SI so p rya

M M'OYI

By a procedure similar to that given in Auxiliary Example 2, the title compound (2.3 g, 77 90) was obtained as a pale yellow solid from the compound

Auxiliary Example 125 (2.6 g, 11 mmol). "H-NMR (300 MHz, SOS") 5: 1.47 (ZH, t, 9-7.2 Hu), 4.56 (2H, k, 9-7.2 Hz), 7.67 (1H , dd, 9U-8.4, 4.2 Hz), 8.62 (1H, dd, 9U-8.3, 1.9 Hz), 9.21 (1H, dd, 9-42, 1.9 Hz).

Auxiliary Example 127

Preparation of ethyl 4-chloro-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate

SI

Sauces

MM Fr

N

By a method similar to that given in Auxiliary Example 3, the title compound (1.5 g, 71 95) was obtained as a white solid from the compound of Auxiliary

Example 126 (2.2 g, 8.3 mmol). "H-NMR (300 MHz, DMSO-av) 5: 1.31 (ZH, t, 9U-7.1 Hu), 4.37 (2H, k, 9-71 Hu), 7.43 (1H, dd, 9-81, 4,7

Hz), 8.33 (TN, dd, uU-8.1, 1.7 Hz), 8.69 (1H, dd, 9-4.7, 1.7 Hz), 12.88 (IN, w with).

Auxiliary Example 128

Preparation of ethyl 4-chloro-2-oxo-1-(2-oxo-2-phenylethyl)-1,2-dihydro-1,8-naphthyridine-3-carboxylate

SI

So"

MM z o

By a procedure similar to that given in Auxiliary Example 4, the title compound (1.1 g, 51 95) was obtained as a pale yellow oil from the compound of Auxiliary Example 127 (1.5 g, 5.7 mmol). "H-NMR (300 MHz, SOSI") 6: 1.42 (ZH, t, 9-71 Hz), 4.48 (2H, k, 9U-7.1 Hz), 5.98 (2H, s ), 7.27-7.33 (1H,

m), 7.48-7.58 (2Н, m), 7.59-7.69 (1Н, m), 8.02-8.12 (2Н, m), 8.36 (1Н, dd, 9U-8.0, 1.8 Hu), 8.54 (1H, dd, 9U-4.7, 1.7 Hu).

Auxiliary Example 129

Preparation of 3-hydroxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo|3,2-cI1,v6|Inaphthyridine-2-carboxylate

Me, b

SCHE schu TON and and WE Me) x

By a procedure similar to that given in Auxiliary Example 33, the title compound (653 mg, 55 95) was obtained as a pale yellow solid from the compound

Auxiliary Example 128 (1.1 g, 2.9 mmol). "H-NMR (300 MHz, SOS") 6: 1.45 (ZH, t, 9U-7.1 Hz), 4.36 (ZH, s), 4.46 (2H, k, U-7, 2 Gu), 6.00 (2H, s), 7.20 (1H, dd, 9-7.9, 4.7 Hz), 7.45-7.58 (2H, m), 7.58- 7.69 (1H, m), 8.02-8.15 (2H, m), 8.33-8.51 (2H, m), 8.70 (IN, s).

Auxiliary Example 130

Preparation of 3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo|3,2-cI1,v6|Inaphthyridine-2-carboxylate

Me, SO, EI

M

MM Zo and

By a procedure similar to that given in Auxiliary Example 115, the title compound (420 mg, 79 95) was obtained as a white solid from the compound of Auxiliary

Example 129 (512 mg, 1.3 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.35 (ЗН, t, 9-71 Hz), 3.91 (ЗН, s), 4.24-4.44 (5Н, m), 5.97 (2H, s), 7.36 (IN, dd, 9U-8.1, 4.5 Hz), 7.55-7.69 (2H, m), 7.68-7.82 ( 1H, m), 8.06-8.24 (2H, m), 8.46 (1H, dd, 9-4.6, 1.4

Hz), 8.75 (TN, dd, U-8.1, 1.5 Hz).

Auxiliary Example 131

Preparation of 3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo|3,2-cI1,6Inaphthyridine-2-carboxylic acid

Me, Don

M class

M M c) and

By a procedure similar to that given in Auxiliary Example 7, the title compound (264 mg, 75 95) was obtained as a white solid from the compound of Auxiliary

Example 130 (380 mg, 0.91 mmol). "H-NMR (300 MHz, DMSO-dv) 6: 3.90 (ZH, s), 4.32 (ZH, s), 5.97 (2H, s), 7.35 (1H, dd, 9U -8.1, 4.7 Hu), 7.54-7.68 (2Н, m), 7.69-7.81 (1Н, m), 8.03-8.27 (2Н, m), 8.33-8.56 (1H, m), 8.75 (1H, d, 9U-7.2 Hz), 13.04 (IN,

w c).

Auxiliary Example 132

Production of methyl 4-aminopyridine-3-carboxylate

CO

And I hmm

By a procedure similar to that given in Auxiliary Example 124, the title compound (4.9 g, 89 95) was obtained as a pale yellow solid from 4-aminopyridine-

3-carboxylic acid (5.0 g, 36 mmol), sulfuric acid (36 mL), and methanol (72 mL). "H-NMR (300 MHz, SOSI33) 6: 3.91 (ZH, s), 6.20 (2H, w s), 6.51 (1H, d, 9-5.9 Hz), 8.20 (1H, d, 9-6.0 Hz), 8.90 (1H, s).

Auxiliary Example 133

Preparation of ethyl 4-hydroxy-2-oxo-1,2-dihydro-1,6-naphthyridine-3-carboxylate

So"

And mo

N

By a procedure similar to that given in Auxiliary Example 1, the title compound (3.5 g, 49 95) was obtained as a pale yellow powder from the compound of Auxiliary Example 132 (4.7 g, 31 mmol). "H-NMR (300 MHz, DMSO-av) 6: 1.28 (ZH, t, 9U-7.1 Hz), 4.26 (2H, k, 9-7.0 Hz), 7.20 ( 1H, d, 9U-6.0 Hz), 8.50 (1H, d, 9U-6.0 Hz), 8.92-9.09 (1H, m), 11.66 (T1H, w s) .

Auxiliary Example 134

Preparation of ethyl 2,4-dichloro-1,6-naphthyridine-3-carboxylate

SI melts

By a procedure similar to that given in Auxiliary Example 2, the title compound (2.7 g, 66 95) was obtained as a pale yellow solid from the compound

Auxiliary Example 133 (3.5 g, 15 mmol). "H-NMR (300 MHz, SOS Iv) 6: 1.47 (ZH, t, 9U-7.2 Hz), 4.56 (2H, k, 9-71 Hz), 7.87 (1H, dd , U-5.9,0.8 Hu), 8.92 (1H, d, 9U-5.9 Hz), 9.66 (1H, d, U-0.9 Hu).

Auxiliary Example 135

Preparation of ethyl 4-chloro-2-oxo-1,2-dihydro-1,6-naphthyridine-3-carboxylate

S se and hmm Zo n

By a procedure similar to that given in Supplementary Example 3, the title compound (733 mg, 30 95) was obtained as a pale brown solid from the compound

Auxiliary Example 134 (2.6 g, 9.7 mmol). "H-NMR (300 MHz, DMSO-av) 6: 1.31 (ZH, t, 9U-7.1 Hz), 4.36 (2H, k, 9-7.1 Hu), 7.29 ( 1H, d, 9U-5.7 Hz), 8.63 (1H, d, 9U-5.7 Hz), 9.06 (1H, s), 12.72 (AN, w s).

Auxiliary Example 136

Production of ethyl 4-chloro-2-oxo-1-(2-oxo-2-phenylethyl)-1,2-dihydro-1,6-naphthyridine-3-carboxylate

SI and mo x

By a procedure similar to that given in Auxiliary Example 4, the title compound (344 mg, 33 95) was obtained as a pale yellow solid from the compound

Auxiliary Example 135 (710 mg, 2.8 mmol). "H-NMR (300 MHz, SOSI") 6: 1.42 (ZH, t, 9-72 Hz), 4.48 (2H, k, 9U-7.2 Hz), 5.73 (2H, s ), 6.86 (1H, d, y-5.9 Hz), 7.49-7.63 (2H, m), 7.64-7.79 (1H, m), 7.95-8, 19 (2H, m), 8.64 (1H, w s), 9.30 (IN, w s).

Auxiliary Example 137

Preparation of 3-hydroxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo|3,2-cI1,bInaphthyridine-2-carboxylate

Me сОЖж!

M Uh and zmo

A mixture of the compound of Auxiliary Example 136 (574 mg, 1.6 mmol), sarcosine ethyl ester hydrochloride (286 mg, 1.9 mmol), triethylamine (0.65 mL, 4.7 mmol), and ethanol (29 mL) was heated at reflux Refrigerate for 2.5 hours. Sarcosine ethyl ester hydrochloride (286 mg, 1.9 mmol) and triethylamine (0.43 mL, 3.1 mmol) were then added and the mixture was heated at reflux for 5.5 hours. Sarcosine ethyl ester hydrochloride (286 mg, 1.9 mmol) and triethylamine (0.65 mL, 4.7 mmol) were added and the mixture was heated at reflux for 46 hours. Triethylamine (0.65 mL, 4.7 mmol) was added and the mixture was heated at reflux for 3 hours. Triethylamine (0.65 mL, 4.7 mmol) was added and the mixture was heated at reflux for 64 hours. Triethylamine (0.65 mL, 4.7 mmol) was then added and the mixture was heated at reflux for 3 hours. Triethylamine (0.65 mL, 4.7 mmol) was then added and the mixture was heated at reflux for 3 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was acidified with 20 95 aqueous citric acid solution and stirred for 30 minutes while cooling on ice. The resulting solid was collected by filtration, the resulting solid was washed with water and dried under reduced pressure. The solid was washed with a solvent mixture of ethyl acetate-hexane and hexane to give the title compound (485 mg, 77 95) as a pale brown powder. "H-NMR (300 MHz, DMSO-av) 6: 1.34 (ZH, t, 9U-7.1 Gu), 4.27-4.43 (5H, m), 5.91 (2H, s ), 7.42 (1H, d, 3-6.0 Hz), 7.58-7.69 (2H, m), 7.71-7.82 (1H, m), 8.08-8, 23 (2H, m), 8.50 (1H, d, U-5.9 Hz), 9.07 (1H, w s), 9.49 (1H, s).

Auxiliary Example 138

Preparation of 3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo

IZ,2-cIP1,b|Inaphthyridine-2-carboxylate

Me, SO

M

H

And so am I

By a procedure similar to that given in Auxiliary Example 115, the title compound (313 mg, 64 95) was obtained as a white solid from the compound of Auxiliary

Example 137 (471 mg, 1.2 mmol). "H-NMR (300 MHz, DMSO-av) 6: 1.35 (ZH, t, 9U-6.0 Hz), 3.88 (ZH, s), 4.28-4.40 (5H, m ), 5.94 (2H, s), 7.43 (1H, d, 9U-6.0 Gu), 7.59-7.69 (2H, m), 7.72-7.82 (1H, m), 8.11-8.22 (2H, m), 8.51 (IN, d, uU-6.0 Hz), 9.52 (IN, s).

Auxiliary Example 139

Preparation of 3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo

IZ,2-cIP1,6|Inaphthyridine-2-carboxylic acid

Me. Bon

M

They are also mo x

By a procedure similar to that given in Auxiliary Example 7, the title compound (259 mg, 92 95) was obtained as a white solid from the compound of Auxiliary

Example 138 (301 mg, 0.72 mmol). "H-NMR (300 MHz, DMSO-α) 5: 3.87 (ZH, s), 4.36 (ZH, s), 5.94 (2H, s), 7.42 (1H, d, 9U -6.0 Hz), 7.57-7.70 (2H, m), 7.71-7.83 (1H, m), 8.07-8.26 (2H, m), 8.49 ( 1H, d, U-5.9 Hz), 9.51 (1H, s), 13.01 (1H, w s).

Auxiliary Example 140

Production of ethyl b-ethyl-3-hydroxy-1-methyl-4-oxo-4,5-dihydro-1H-pyrrolo|3,2-c|Ipyridine-2-carboxylate

Soybeans

M

EN M OTO

N

By a procedure similar to that given in Auxiliary Example 40, the title compound (4.87 g, 85 90) was obtained as a brown powder from the compound of Auxiliary Example 38 (5.00 g, 21.8 mmol). "H-NMR (300 MHz, DMSO- av) 5: 1.18 (ZN, t, U-7.6 Hu), 1.30 (ZN, t, 9U-7.1 Hu), 2.39- 2.49 (2H, m), 3.73 (ZH, s), 4.29 (2H, k, 9-71 Hz), 6.25 (1H, s), 8.87 (IN, w s) , 10.81 (1H, w s).

Auxiliary Example 141

Production of ethyl b-ethyl-1-methyl-4-oxo-3-(2,2,2-trifluoroethoxy)-4,5-dihydro-1H-pyrroloyl3,2-sipyridine-2-carboxylate

Me, SO h lov, v

EN MOTO

N

A mixture of the compound of Auxiliary Example 140 (200 mg, 0.757 mmol), cesium carbonate (271 mg, 0.832 mmol), 2,2,2-trifluoroethyltrifluoromethanesulfonate (0.109 mL, 0.757 mmol), dimethyl sulfoxide (2.0 mL), and DMF (2, 0 mL) was stirred at 60 °C for 2 h. The reaction mixture was diluted with water and the precipitated solid was collected by filtration. The resulting solid was washed with water and diisopropyl ether and dried under reduced pressure to give the title compound (161 mg, 61 95) in the form of a white solid. "H-NMR (300 MHz, DMSO-αv) 5: 1.19 (ZN, t, 9U-7.5 Hu), 1.27 (ZN, t, U- 7.0 Hu), 2.51-2.56 (2H, m), 3.79 (ZH, s), 4.24 (2H, k, 9-7.0 Hz), 4.97 (2H, k, 9U-9.3 Gu), 6.38 (1H, s), 11.06 (IN, w s).

Auxiliary Example 142

Preparation of ethyl b-ethyl-5-(33-methoxybenzyl)-1-methyl-4-oxo-3-(2,2,2-trifluoroethoxy)-4,5-dihydro-1H-pyrroloY3,2-c|Ipyridine- 2-carboxylate

Me, SO and r

WITH

- M M s); from"

A mixture of the compound of Auxiliary Example 141 (500 mg, 1.44 mmol), sodium tert-butoxide (180 mg, 1.87 mmol), lithium bromide (250 mg, 2.88 mmol), 1-(chloromethyl)-3-methoxybenzene (0.313 ml, 2.16 mmol), OME (8.0 ml) and DMF (2.0 ml) were stirred at 60 "C for 13 hours. Water (50 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed saturated brine, dried over sodium sulfate and concentrated under reduced pressure.The residue was purified by silica gel chromatography (eluate; ethyl acetate/hexane-3/97-70/30) to give the title compound (508 mg, 76 95) in in the form of a yellow oil. "H-NMR (300 MHz, DMSO-α) 6: 1.14-1.36 (6Н, m), 2.60 (2Н, k, 9-7.2 Hz), 3.70 (ZH, s), 3.85 (ZH, s), 4.26 (2H, k, 9-7.2 Hz), 4.89 (2H, k, U-9.3 Gu), 5.28 (2H, w s), 6.44-6.67 (ZH, m), 6.74-6.95 (1H, m), 7.22 (1H, t, uU-7.9 Gu).

Auxiliary Example 143

Preparation of b-ethyl-5-(3-methoxybenzyl)-1-methyl-4-oxo-3-(2,2,2-trifluoroethoxy)-4,5-dihydro-1H-pyrrolo|3,2-s| Ipyridine-2-carboxylic acid

Me, Son de sv v - M M s); from"

By a procedure similar to that of Sub-Example 49, the title compound (333 mg, 66 95) was prepared as a white powder from the compound of Sub-Example 142 (508 mg, 1.09 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.17 (ZH, t, U-7.3 Hu), 2.60 (2H, k, 9U-7.3 Hz), 3.70 ( ЗН, s), 3.85 (ЗН, s), 4.87 (2Н, к, 9U-9.4 Гу), 5.30 (2Н, w s), 6.43-6.67 (ЗН, m), 6.81 (1H, dd, 9U-7.9, 2.3 Gu), 7.22 (1H, t, 9U-7.9 Gu, 12.70 (IN, w s).

Auxiliary Example 144

Production of ethyl 5-benzyl-6-ethyl-1-methyl-4-oxo-3-(2,2,2-trifluoroethoxy)-4,5-dihydro-1H-pyrrolo|3,2-c|Ipyridine-2 -carboxylate

Me SOI m EVERYTHING

WITH

E IM)

Vp

By a procedure similar to that given in Auxiliary Example 142, the title compound (312 mg, 62 95) was obtained as a yellow oil from the compound of Auxiliary Example 141 (400 mg, 1.16 mmol) and benzyl bromide (0.207 mL, 1 .74 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.16 (ZN, t, 9U-7.3 Hz), 1.29 (ZN, t, 9U-7.1 Hu), 2.61 ( 2H, k, 9-7.3 Gu), 3.85 (ZH, s), 4.26 (2H, k, 9-7.1 Hz), 4.89 (2H, k, 9U-9.3 Hz), 5.34 (2H, w s), 6.54 (1H, s), 7.03-7.09 (2H, m), 7.20-7.27 (1H, m), 7, 28-7.36 (2H, m).

Auxiliary Example 145

Preparation of 5-benzyl-6-ethyl-1-methyl-4-oxo-3-(2,2,2-trifluoroethoxy)-4,5-dihydro-1H-pyrrolo|3,2- c|Ipyridine-2- carboxylic acid

Me, Son x ALL in

Hey M (c)

Vp

By a procedure similar to that of Sub-Example 49, the title compound (213 mg, 73 95) was prepared as a white powder from the compound of Sub-Example 144 (312 mg, 0.715 mmol). "H-NMR (300 MHz, DMSO-av) 6: 1.16 (ZH, t, U-7.3 Hz), 2.60 (2H, k, 9U-7.3 Hu), 3.85 ( ЗН, с), 4.87 (2Н, k, 99.3 Gu), 5.34 (2Н, с с), 6.52 (1Н, с), 7.01-7.10 (2Н, m) , 7.17-7.39 (ZN, m), 12.73 (IN, w s).

Auxiliary Example 146

Preparation of ethyl 5-(2,5-dimethoxybenzyl)-6-ethyl-1-methyl-4-oxo-3-(2,2,2-trifluoroethoxy)-4,5-dihydro-1H-pyrroloyi3,2-c| Ipyridine-2-carboxylate

Me SO

MU and St

WITH

EE m so pu

Meow

By a procedure similar to that given in Auxiliary Example 142, the title compound (121 mg, 21 95) was obtained as a white powder from the compound of Auxiliary Example 141 (400 mg, 1.16 mmol) and 2-(chloromethyl)- 1,4-dimethoxybenzene (325 mg, 1.74 mmol). "H-NMR (300 MHz, DMSO-α) 5: 1.17 (ZN, t, 9-7.3 Hz), 1.29 (ZN, t, 9-7.2 Hu), 2.53- 2.61 (2H, m), 3.56 (ZH, s), 3.83 (ZH, s), 3.86 (ZH, s), 4.26 (2H, k, 9-7.2 Hz ), 4.87 (2H, k, U-9.3 Hz), 5.19 (2H, w s), 5.93 (1H, d, 93.0 Hz), 6.58 (1H, s) , 6.79 (1H, dd, 9U-8.9, 3.0 Hz), 6.97 (1H, d, U-8.9 Hz).

Auxiliary Example 147

Preparation of 5-(2,5-dimethoxybenzyl)-6-ethyl-1-methyl-4-oxo-3-(2,2,2-trifluoroethoxy)-4,5-dihydro-1H-pyrrolyl3,2-c|Ipyridine -2-carboxylic acid

Me, Son ba Shchi s Ge;

EN MOTO

Meow

By a procedure similar to that given in Auxiliary Example 49, the title compound (82.7 mg, 72 95) was obtained as a white powder from the compound of Auxiliary Example 146 (121 mg, 0.244 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.17 (ZH, t, 9-7.3 Hz), 2.52-2.60 (2H, m), 3.56 (ZH, s ), 3.83 (ZH, s), 3.86 (ZH, s), 4.85 (2H, k, 9U-9.3 Gu), 5.19 (2H, w s), 5.92 ( 1H, d, 9-3.0 Hz), 6.56 (1H, s), 6.79 (1H, dd, uU-9.0, 3.0 Hz), 6.97 (1H, d, 9U -9.0 Hz), 12.74 (IN, w s).

Auxiliary Example 148

Preparation of ethyl 4-chloro-b-ethyl-1-(2-(3-methoxyphenyl)-2-oxoethyl|-2-oxo-1,2-dihydropyridine-3-carboxylate

SI note

Her m o

H

Ome

By a procedure similar to that given in Auxiliary Example 142, the title compound (879 mg, 53 95) was obtained as a yellow oil from the compound of Auxiliary Example 38 (1.00 g, 4.35 mmol) and 2-bromo- 1-(33-methoxyphenyl)ethanone (1.99 g, 8.71 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.13 (ZN, t, 9U-7.4 Hz), 1.24 (ZN, t, 9U-7.1 Hu), 2.61 ( 2H, k, 9-74 Gu), 3.85 (ZH, s), 4.25 (2H, k, 9-7.1 Hz), 5.60 (2H, s), 6.44 (1H, c), 7.28-7.35 (1H, m), 7.48-7.59 (2H, m), 7.66-7.74 (IN, m).

Auxiliary Example 149

Preparation of ethyl b-ethyl-3-hydroxy-5-(2-(3-methoxyphenyl)-2-oxoethyl|-1-methyl-4-oxo-4,5-dihydro-1H-pyrroloY3,2-c|Ipyridine- 2-carboxylate

Me, SO

M ba Y

E I. Shk c)

H

Ome

By a procedure similar to that given in Auxiliary Example 40, the title compound (526 mg, 55 95) was obtained as a green powder from the compound of Auxiliary Example 148 (879 mg, 2.33 mmol). "H-NMR (300 MHz, DMSO-α) 5: 1.18 (ZN, t, 9-74 Hz), 1.31 (ZN, t, 9-7.1 Hu), 2.52-2, 61 (2Н, m), 3.80 (ЗН, с), 3.85 (ЗН, с), 4.30 (2Н, k, 957.1 Gu), 5.54 (2Н, с), 6, 43 (1H, s), 7.26-7.36 (1H, m), 7.48-7.60 (2H, m), 7.68-7.76 (1H, m), 8.89 ( IN, w c).

Auxiliary Example 150

Preparation of ethyl 6b-ethyl-5-(2-(3-methoxyphenyl)-2-oxoethyl|-1-methyl-4-oxo-3-(2,2,2-trifluoroethoxy)-4,5-dihydro-1H- pyrrolo|3,2-s|Ipyridine-2-carboxylate

Me SsoOJ them all in

And their MM is)

I

Ome

A mixture of the compound of Auxiliary Example 149 (470 mg, 1.14 mmol), cesium carbonate (446 mg, 1.37 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.197 mL, 1.37 mmol) and DMF (4.7 mL ) was stirred at room temperature for 1 hour. The reaction mixture was diluted with water and the precipitated solid was collected by filtration. The resulting solid was washed with water, diisopropyl ether and ethanol and dried under reduced pressure to give the title compound (423 mg, 75 95) as a green powder. "H-NMR (300 MHz, DMSO-α) 6: 1.19 (ZN, t, 9U-7.3 Hz), 1.28 (ZN, t, 9U-7.2 Hu), 2.59 ( 2H, k, 9-7.3 Hu), 3.83-3.90 (6H, m), 4.26 (2H, k, 927.2 Hu), 4.83 (2H, k, 9-9 ,3 Hz), 5.61 (2H, s), 6.55 (1H, s), 7.27-7.34 (1H, m), 7.48-7.61 (2H, m), 7 ,68-7,76 (1H, m).

Auxiliary Example 151

Preparation of b-ethyl-5-(2-(3-methoxyphenyl)-2-oxoethyl|-1-methyl-4-oxo-3-(2,2,2-trifluoroethoxy)-4,5-dihydro-1H-pyrrolo |3,2-s|Ipyridine-2-carboxylic acid

Me, a dream in the SEZ in

EE m o

I

Ome

By a procedure similar to that of Sub-Example 49, the title compound (300 mg, 86 95) was prepared as a brown powder from the compound of Sub-Example 150 (370 mg, 0.748 mmol). "H-NMR (300 MHz, DMSO-α) 5: 1.19 (ZH, t, 9-7.3 Hz), 2.58 (2H, k, 9-7.3 Hz), 3.83- 3.91 (6H, m), 4.82 (2H, k, 9U-9.3 Hz), 5.60 (2H, s), 6.54 (1H, s), 7.26-7.37 (1H, m), 7.47-7.62 (2H, m), 7.67-7.83 (1H, m), 12.70 (IN, w s).

Auxiliary Example 152

Preparation of ethyl 4-chloro-1-(2-(3-chlorophenyl)-2-oxoethyl|-6-ethyl-2-oxo-1,2-dihydropyridine-3-carboxylate from seeds Shk s)

I

SI

By a procedure similar to that given in Auxiliary Example 142, the title compound (486 mg, 29 95) was obtained as a white powder from the compound of Auxiliary Example 38 (1.50 g, 6.53 mmol) and 2-bromo- of 1-(3-chlorophenyl)ethanone (2.02 g, 8.65 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.14 (ZN, t, U-7.4 Hz), 1.24 (ZN, t, 9U-7.1 Hu), 2.63 ( 2H, k, U-7.4 Hu), 4.25 (2H, k, 97.1 Hz), 5.61 (2H, s), 6.45 (1H, s), 7.59-7, 70 (1N, m), 7.77-7.86 (1N, m), 8.00-8.07 (1N, m), 8.08-8.17 (1N, m).

Auxiliary Example 153

Preparation of ethyl 5-(2-(3-chlorophenyl)-2-oxoethyl|-b-ethyl-3-hydroxy-1-methyl-4-oxo-4,5-dihydro-1H-pyrrolo|3,2-s Ipyridine-2-carboxylate

Me, SOY

M

X ha Y - M M s)

I

SI

By a procedure similar to that given in Auxiliary Example 40, the title compound (460 mg, 87 90) was obtained as a green powder from the compound of Auxiliary Example 152 (486 mg, 1.27 mmol). "H-NMR (300 MHz, DMSO-av) 6: 1.18 (ZN, t, 9U-7.4 Hz), 1.31 (ZN, t, 9U-7.0 Hz), 2.57 ( 2H, k, U-7.4 Hu), 3.80 (ZH, s), 4.30 (2H, k, 9-7.0 Hu), 5.53 (2H, s), 6.44 ( 1H, s), 7.61-7.68 (1H, m), 7.80 (1H, ddd, uU-7.8, 2.0, 0.9 Hz), 8.05 (TN, dt, U-7.8, 0.9 Hz), 8.13 (1TN, t, U-2.0 Hz), 8.90 (1Н, s).

Auxiliary Example 154

Preparation of ethyl 5-(2-(3-chlorophenyl)-2-oxoethyl|-b-ethyl-1-methyl-4-oxo-3-(2,2,2-trifluoroethoxy)-4,5-dihydro-1H- pyrrolo|3,2-s|Ipyridine-2-carboxylate

Me, SOJ

M

In LY se

ETO

I

SI

By a procedure similar to that given in Auxiliary Example 150, the title compound (348 mg, 63 95) was obtained as a green powder from the compound of Auxiliary Example 153 (460 mg, 1.10 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.19 (ZN, t, 9U-7.3 Hz), 1.28 (ZN, t, 9U-7.1 Hu), 2.60 ( 2H, k, 9-7.3 Gu), 3.86 (ZH, s), 4.26 (2H, k, 9-7.1 Hz), 4.83 (2H, k, 9U-9.3 Hz), 5.61 (2H, s), 6.56 (1H, s), 7.61-7.69 (1H, m), 7.78-7.84 (IN, m), 8.03 -8.09 (1H, m), 8.14 (1H, t, 9U-1.7 Gu).

Auxiliary Example 155

Preparation of 5-(2-(3-chlorophenyl)-2-oxoethyl|-b-ethyl-1-methyl-4-oxo-3-(2,2,2-trifluoroethoxy)-4,5-dihydro-1H-pyrrolyl3 ,2-s|Ipyridine-2-carboxylic acid

Me, Song wang z

E ih M c) y

SI

By a procedure similar to that of Sub-Example 49, the title compound (192 mg, 59 95) was obtained as a brown powder from the compound of Sub-Example 154 (348 mg, 0.698 mmol). "H-NMR (300 MHz, DMSO-α) 5: 1.19 (ZH, t, 9-7.3 Hz), 2.60 (2H, k, 9-7.3 Hz), 3.86 ( ЗН, с), 4.81 (2Н, k, 99.2 Hz), 5.60 (2Н, с), 6.55 (1Н, с), 7.58-7.71 (1Н, m), 7.76-7.86 (1H, m), 8.00-8.10 (1H, m), 8.14 (1H, t,

U-1.7 Gu), 12.72 (IN, w s).

Auxiliary Example 156

Preparation of ethyl b-ethyl-5-(2-methoxybenzyl)-1-methyl-4-oxo-3-(2,2,2-trifluoroethoxy)-4,5-dihydro-1H-pyrrolo|3,2-s| Ipyridine-2-carboxylate

Me, SO

MU oi-svz v

E ikh She)

MeO -

By a procedure similar to that given in Auxiliary Example 142, the title compound (138 mg, 26 95) was prepared as a white powder from the compound of Auxiliary Example 141 (400 mg, 1.16 mmol) and 1-(chloromethyl)- 2-methoxybenzene (272 mg, 1.74 mmol). "H-NMR (300 MHz, DMSO- av) 5: 1.17 (ZN, t, U-7.4 Hu), 1.29 (ZN, t, 9U-7.1 Hu), 2.53- 2.61 (2Н, m), 3.86 (ЗН, s), 3.688 (ЗН, с), 4.26 (2Н, k, 9-7.1 Gu), 4.86 (2Н, k, U -9.3 Hz), 5.22 (2H, w s), 6.41 (1H, dd, 9U-7,5,1,2

Hz), 6.57 (1H, s), 6.82 (1H, td, U-7.5,0.9 Hu), 7.01-7.09 (1H, m), 7.18-7 ,28 (1H, m).

Auxiliary Example 157

Preparation of b-ethyl-5-(2-methoxybenzyl)-1-methyl-4-oxo-3-(2,2,2-trifluoroethoxy)-4,5-dihydro-1H-pyrrolo|3,2-s| Ipyridine-2-carboxylic acid

Me, dream

MU of Oi-St

EE ih M is)

Meow

By a procedure similar to that of Sub-Example 49, the title compound (104 mg, 80 95) was prepared as a white powder from the compound of Sub-Example 156 (138 mg, 0.296 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.17 (ZH, t, 9-7.3 Hz), 2.53-2.60 (2H, m), 3.86 (ZH, s ), 3.88 (ZH, s), 4.84 (2H, k, U-9.3 Hz), 5.22 (2H, w s), 6.40 (1H, dd, 9U-7.5 , 1.3 Hz), 6.55 (1H, s), 6.82 (1H, td, 97.5, 0.9 Gu), 7.00-7.11 (1H, m), 7.16 -7.31 (1H, m), 12.72 (IN, w s).

Auxiliary Example 158

Preparation of ethyl b-ethyl-5-(4-methoxybenzyl)-1-methyl-4-oxo-3-(2,2,2-trifluoroethoxy)-4,5-dihydro-1H-pyrrolo|3,2-s| Ipyridine-2-carboxylate

Me SoOzh k A SEZ va

E m o

Ome

By a procedure similar to that given in Auxiliary Example 142, the title compound (175 mg, 43 95) was prepared as a white powder from the compound of Auxiliary Example 141 (300 mg, 0.866 mmol) and 1-(chloromethyl)-4- methoxybenzene (0.175 ml, 1.30 mmol). "H-NMR (300 MHz, DMSO-av) 6: 1.16 (ZN, t, 9U-7.2 Hz), 1.29 (ZN, t, 9U-7.2 Hz), 2.62 ( 2H, k, 9-7.2 Hu), 3.71 (ZN, c), 3.84 (ZN, c), 4.26 (2H, k, 9-7.2 Hu), 4.90 ( 2H, k, 9U-9.3 Hz), 5.26 (2H, w s), 6.51 (1H, s), 6.82- 6.92 (2H, m), 6.97-7, 08 (2H, m).

Auxiliary Example 159

Preparation of b-ethyl-5-(4-methoxybenzyl)-1-methyl-4-oxo-3-(2,2,2-trifluoroethoxy)-4,5-dihydro-1H-pyrrolo|3,2-s| Ipyridine-2-carboxylic acid

Me, Son k A SEz

SS

E m o - OMe

By a procedure similar to that of Sub-Example 49, the title compound (157 mg, 96 95) was prepared as a white powder from the compound of Sub-Example 158 (175 mg, 0.375 mmol). "H-NMR (300 MHz, DMSO-α) 5: 1.16 (ZH, t, 9-7.3 Hz), 2.62 (2H, k, 9-7.3 Hz), 3.71 ( ЗН, s), 3.84 (ЗН, s), 4.88 (2Н, k, 9У-9.3 Hz), 5.26 (2Н, в s), 6.49 (1Н, s), 6 .81-6.92 (2H, m), 6.96-7.09 (2H, m), 12.70 (IN, w s).

Auxiliary Example 160

Preparation of ethyl 5-(2-chlorobenzyl)-6-ethyl-1-methyl-4-oxo-3-(2,2,2-trifluoroethoxy)-4,5-dihydro-1H-pyrrolo|3,2-s Ipyridine-2-carboxylate

Me, SO m A SEz c

E m o

In -

By a procedure similar to that given in Auxiliary Example 142, the title compound (163 mg, 30 95) was obtained as a white powder from the compound of Auxiliary Example 141 (400 mg, 1.16 mmol) and 1-chloro-2- (chloromethyl)benzene (0.226 mL, 1.74 mmol). "H-NMR (300 MHz, DMSO- av) 5: 1.18 (ZN, t, U-7.4 Hu), 1.29 (ZN, t, 9U-7.1 Hu), 2.53- 2.62 (2H, m), 3.87 (ZH, s), 4.27 (2H, k, 957.1 Gu), 4.86 (2H, k, 9U-9.3 Hz), 5, 32 (2H, s), 6.55 (1H, dd, 9U-7.6, 1.5 Hz), 6.62 (1H, s), 7.21-7.33 (2H, m), 7 .52 (1H, dd, 9U-7.7, 1.3 Gu).

Auxiliary Example 161

Preparation of 5-(2-chlorobenzyl)-6-ethyl-1-methyl-4-oxo-3-(2,2,2-trifluoroethoxy)-4,5-dihydro-1H-pyrrolo|3,2-s| Ipyridine-2-carboxylic acid

Me, Son m In SEZ c

And their AI c) a

By a procedure similar to that of Sub-Example 49, the title compound (138 mg, 90 95) was prepared as a white powder from the compound of Sub-Example 160 (163 mg, 0.346 mmol). "H-NMR (300 MHz, DMSO-av) 5: 1.18 (ZH, t, 9U-7.4 Hu), 2.52-2.62 (2H, m), 3.87 (ZH, s ), 4.83 (2H, k, 99.3 Gu), 5.32 (2H, s), 6.50 (1H, dd, 9-7.7, 1.6 Hz), 6.60 (1H , c), 7.22-7.33 (2H, m), 7.52 (1H, dd, 9-7.7, 1.3

Hz), 12.76 (IN, w s).

Auxiliary Example 162

Preparation of ethyl 4-chloro-6-ethyl-2-oxo-1-(2-phenylethyl)-1,2-dihydropyridine-3-carboxylate

(Fi uv

E Z)

By a procedure similar to that given in Auxiliary Example 142, the title compound (480 mg, 16 95) was obtained as a white powder from the compound of Auxiliary Example 38 (2.00 g, 8.71 mmol) and (2-bromomethyl )benzene (1.77 ml, 11.3 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.14 (ZN, t, U-7.4 Hz), 1.28 (ZN, t, 9-7.1 Hz), 2.63 ( 2H, k, 9-74 Gu), 2.85-2.93 (2H, m), 4.07-4.15 (2H, m), 4.29 (2H, k, 9-71 Hz), 6.30 (1H, s), 7.19-7.28 (ZH, m), 7.28-7.38 (2H,

M).

Auxiliary Example 163

Preparation of ethyl b-ethyl-3-hydroxy-1-methyl-4-oxo-5-(2-phenylethyl)-4,5-dihydro-1H-pyrrolo|3,2- cIpyridine-2-carboxylate

Me SO

Mka Y

And their Shk c)

By a procedure similar to that given in Auxiliary Example 40, the title compound (481 mg, 80 95) was obtained as a white powder from the compound of Auxiliary Example 162 (480 mg, 1.44 mmol). "H-NMR (300 MHz, DMSO-av) 6: 1.20 (ZN, t, 9U-7.3 Hz), 1.31 (ZN, t, 9U-7.1 Hu), 2.63 ( 2H, k, 9-7.3 Gu), 2.80-2.94 (2H, m), 3.75 (ZH, s), 4.01-4.16 (2H, m), 4.30 (2H, k, 9-7.1 Gu), 6.34 (1H, s), 7.11-7.41 (5H, m), 8.94 (IN, w s).

Auxiliary Example 164

Preparation of ethyl b-ethyl-1-methyl-4-oxo-5-(2-phenylethyl)-3-(2,2,2-trifluoroethoxy)-4,5-dihydro-1H-pyrrolo|3,2-s Ipyridine-2-carboxylate

Me SO

M. H. O

M hundred

E m o

By a procedure similar to that given in Auxiliary Example 150, the title compound (185 mg, 31 95) was obtained as a white powder from the compound of Auxiliary Example 163 (482 mg, 1.31 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.22 (ZN, t, 9U-7.3 Hz), 1.29 (ZN, t, 9U-7.2 Hz), 2.67 ( 2H, k, U9-7.3 Gu), 2.82-2.94 (2H, m), 3.82 (ZH, s), 4.10-4.20 (2H, m), 4.26 (2H, k, U9-7.2 Hz), 4.90 (2H, k, U-9.3 Gu), 6.46 (1H, s), 7.15-7.38 (5H, m) .

Auxiliary Example 165

Preparation of b-ethyl-1-methyl-4-oxo-5-(2-phenylethyl)-3-(2,2,2-trifluoroethoxy)-4,5-dihydro-1H-pyrrolo|3,2-c| Ipyridine-2-carboxylic acid

Me, dream

M. H. O.:

M.Ed

Oh)

By a procedure similar to that of Sub-Example 49, the title compound (143 mg, 83 95) was obtained as a brown powder from the compound of Sub-Example 164 (185 mg, 0.411 mmol). "H-NMR (300 MHz, DMSO-av) 5: 1.21 (ZH, t, U-7.2 Gu), 2.66 (2H, k, 9-72 Hz), 2.81-2, 94 (2H, m), 3.81 (ZN, s), 4.05-4.30 (2H, m), 4.89 (2H, k, 9U-9.3 Gu), 6.44 (1H , c), 7.09-7.48 (5H, m), 12.67 (IN, w c).

Auxiliary Example 166

Preparation of ethyl 5-(3Z-chlorobenzyl)-6-ethyl-1-methyl-4-oxo-3-(2,2,2-trifluoroethoxy)-4,5-dihydro-1H-pyrrolo|3,2-s Ipyridine-2-carboxylate

Soybeans

MU i-sez v

E ih M s) se

By a procedure similar to that given in Auxiliary Example 142, the title compound (325 mg, 60 95) was prepared as a white powder from the compound of Auxiliary Example 141 (400 mg, 1.16 mmol) and 1-chloro-3- (chloromethyl)benzene (357 mg, 1.74 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.17 (ZN, t, U-7.4 Hz), 1.29 (ZN, t, 9U-7.1 Hu), 2.60 ( 2H, k, 9-71 Hu), 3.85 (ZN, c), 4.26 (2H, k, 9U-7.4 Hu), 4.88 (2H, k, U-9.3 Hu) , 5.33 (2H, w s), 6.56 (1H, s), 6.96-7.05 (1H, m), 7.10-7.18 (1H, m), 7.27- 7.43 (2H, m).

Auxiliary Example 167

Preparation of 5-(33-chlorobenzyl)-6-ethyl-1-methyl-4-oxo-3-(2,2,2-trifluoroethoxy)-4,5-dihydro-1H-pyrrolo|3,2-s| Ipyridine-2-carboxylic acid

Me, Sleep is bad

The same

E ikh She) u

By a procedure similar to that of Sub-Example 49, the title compound (281 mg, 92 95) was prepared as a white powder from the compound of Sub-Example 166 (325 mg, 0.690 mmol). "H-NMR (300 MHz, DMSO-av) 6: 1.17 (ZH, t, U-7.2 Hz), 2.60 (2H, k, 9-7.2 Hu), 3.85 ( ЗН, с), 4.86 (2Н, k, 99.3 Gu), 5.34 (2Н, w с), 6.54 (1Н, с), 6.95-7.05 (1Н, m) , 7.10-7.18 (1H, m), 7.26-7.43 (2H, m), 12.74 (1H, s).

Auxiliary Example 168

Preparation of ethyl 5-(4-chlorobenzyl)-6-ethyl-1-methyl-4-oxo-3-(2,2,2-trifluoroethoxy)-4,5-dihydro-1H-pyrrolo|3,2-s Ipyridine-2-carboxylate

Me, So

MU ie v

EE ih SHY c) yo

By a procedure similar to that given in Auxiliary Example 142, the title compound (213 mg, 39 95) was prepared as a white powder from the compound of Auxiliary Example 141 (400 mg, 1.16 mmol) and 1-chloro-4- (chloromethyl)benzene (357 mg, 1.74 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.16 (ZN, t, 9U-7.3 Hz), 1.29 (ZN, t, 9U-7.1 Hu), 2.60 ( 2H, k, 9-71 Hu), 3.85 (ZN, c), 4.26 (2H, k, 957.3 Hu), 4.88 (2H, k, U-9.3 Hu), 5 .32 (2H, w s), 6.55 (1H, s), 7.03-7.16 (2H, m), 7.66-7.43 (2H, m).

Auxiliary Example 169

Preparation of 5-(4-chlorobenzyl)-6-ethyl-1-methyl-4-oxo-3-(2,2,2-trifluoroethoxy)-4,5-dihydro-1H-pyrrolo|3,2-s| Ipyridine-2-carboxylic acid

Me, Son

In i-sva v

E their M c) - SI

By a procedure similar to that of Sub-Example 49, the title compound (188 mg, 94 95) was prepared as a white powder from the compound of Sub-Example 168 (213 mg, 0.452 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.16 (ZH, t, U-7.3 Hz), 2.59 (2H, k, 9U-7.3 Hu), 3.84 ( ЗН, с), 4.86 (2Н, k, 99.3 Gu), 5.32 (2Н, w с), 6.53 (1Н, с), 7.01-7.20 (2Н, m) , 7.28-7.49 (2H, m), 12.75 (IN, w s).

Auxiliary Example 170

Preparation of 33-ethoxy-b-ethyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno|3,2-c|pyridine-2-carboxylate

SO, uoa udkotsi

ZM Me) r

By a method similar to the method given in Auxiliary Example 5, ethyl b-ethyl-3-hydroxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno|3,2-s| Ipyridine-2-carboxylate was prepared from the compound of Auxiliary Example 39 (3.6 g, 10.3 mmol), ethyl thioglycolate (14.44 mL, 103 mmol) and triethylamine (2.3 mL, 20.6 mmol). The title compound (900 mg, 47 95) was obtained as a white solid from the thus obtained ethyl 6b-ethyl-3-hydroxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5 -dihydrothienoIII,2-c|Ipyridine-2-carboxylate (1.8 g, 4.7 mmol) using a method similar to that given in Auxiliary Example 43. "H-NMR (300 MHz, DMSO-α) 5: 1 ,17 (ZN, t, U-7.4 Hu), 1.23-1.36 (6H, m), 2.61 (2H, k, 9U-7.4 Hu), 4.14 (2H, k, 9-71 Gu), 4.28 (2H, k, 97.0 Hz), 5.65 (2H, s), 6.83 (1H, s), 7.62 (2H, t, 9U- 7.6 Hz), 7.70-7.79 (1H, m), 8.12 (2H, d, 9-7.2 Gu).

Auxiliary Example 171

Preparation of 3-(2,2-difluoroethoxy)-6b-ethyl-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo|3,2- c|Ipyridine-2-carboxylic acid

Me, SO, N

Mshi O EK - vm OtO E rya

By a method similar to that given in Auxiliary Example 56, ethyl 3-(2,2-difluoroethoxy)-6-ethyl-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4, 5-dihydro-1H-pyrrolo|3,2-c|pyridine-2-carboxylate was obtained from the compound of Auxiliary Example 40 (500 mg, 1.31 mmol), 2,2-difluoroethyltrifluoromethanesulfonate (336 mg, 1.57 mmol) and cesium carbonate (554 mg, 1.70 mmol).

The title compound (314 mg, 83 95) was obtained as a white powder from thus obtained ethyl 3-(2,2-difluoroethoxy)-6b-ethyl-1-methyl-4-oxo-5-(2-oxo- 2-phenylethyl)-4,5-dihydro-1H-pyrrolo|3,2-c|Ipyridine-2-carboxylate (400 mg, 0.90 mmol) using a method similar to that given in Auxiliary Example 59. "H - NMR (300 MHz, DMSO- av) 5: 1.19 (ZN, t, 9U-7.2 Hu), 2.58 (2H, k, 9U-7.3 Hu), 3.85 (ZN, c), 4.40 (2H, td,

U-14.6, 1.2 Hz), 5.60 (2H, s), 6.26 (1H, tt, 9U-55.0, 3.9 Gu), 6.77 (1H, s), 7.58-7.76 (ZH, m), 8.12 (2H, d, 9-7.5

Hz), 12.50-12.70 (1H, pc).

Auxiliary Example 172

Preparation of ethyl b-ethyl-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-3-propoxy-4,5-dihydro-1H-pyrrolo|3,2-c|Ipyridine-2 -carboxylate

SOEs r

They are still (0) eaten in M (in) Me with

By a procedure similar to that given in Auxiliary Example 56, the title compound (177 mg, 83 95) was obtained as a brown powder from the compound of Auxiliary Example 40 (191 mg, 0.50 mmol), dipropyl sulfate (364 mg, 2 .0 mmol), potassium carbonate (414 mg, 3.0 mmol) and acetone (20 ml). "H-NMR (300 MHz, SOCIz) 6: 1.01 (3 H, t, 9-7.5 Hz), 1.28 (ZN, t, 9-7.3 Hz), 1.40 (ZN ) , 4.21 (2 N, t, U-6.7 Hz), 4.36 (2 N, k, 9 U-7.2 Hz), 5.59 (2 N, s), 6.19 (1 N , c), 7.47-7.56 (2 N, m), 7.59-7.67 (1 N, m), 8.02-8.09 (2N, m).

Auxiliary Example 173

Preparation of b-ethyl-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-3-propoxy-4,5-dihydro-1H-pyrrolo|3,2- c|Ipyridine-2- carboxylic acid

Me, SO, Nn

M c 6)

Ba Z o) Measure

By a procedure similar to that given in Auxiliary Example 59, the title compound (237 mg, 93 95) was obtained as a pale yellow powder from the compound of Auxiliary Example

172 (274 mg, 0.65 mmol). "H-NMR (300 MHz, DMSO-dv) 5: 0.91 (ZH, t, 9U-7.5 Hz), 1.18 (ZH, t, 9U-7.3 Hz), 1.55 -1.70 (2H, m), 2.57 (2 H, k, 9-74 Hu), 3.84 (Z H, s), 4.07 (2 H, t, U-6.5 Hu ), 5.58 (2 N, s), 6.47 (1 N, s), 7.56-7.66 (2 N, m), 7.69-7.78 (1 N, m), 8.07-8.16 (2H, m), 12.42 (1H, s).

Auxiliary Example 174

Preparation of b-ethyl-1-methyl-3-(1-methylethoxy)-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo|3,2-c| Ipyridine-2-carboxylic acid

Me, SO, N

MORE fe; oh yes

E M'STO Me rya

By a method similar to the method given in Auxiliary Example 56, ethyl b-ethyl-1-methyl-3-(1-methylethoxy)-4-oxo-5-(2-oxo-2-phenylethyl)-4,5- dihydro-1H-pyrrolo|Y3,2-c|Ipyridine-2-carboxylate (291 mg, 46 95) was obtained as a pale purple powder from the compound of Auxiliary Example 40 (574 mg, 1.50 mmol), potassium carbonate (1 .04 g, 7.5 mmol) and diisopropyl sulfate (1.37 g, 7.5 mmol).

The title compound (242 mg, 97 95) was obtained as a colorless powder from the thus obtained ethyl b-ethyl-1-methyl-3-(1-methylethoxy)-4-oxo-5-(2-oxo-2- phenylethyl)-4,5-dihydro-1H-pyrrolo|3,2-c|Ipyridine-2-carboxylate (267 mg, 0.63 mmol) using a method similar to that given in Auxiliary Example 59. "H-NMR (300 MHz, DMSO-av) 6: 1.13-1.23 (9 N, m), 2.57 (2 N, k, 9-7.5 Hz), 3.84 (Z N, s) , 4.65-4.80 (1N, m), 5.58 (2N, s), 6.47 (1N, s), 7.56-7.66 (2N, m), 7, 69-7.78 (1 N, m), 8.07-8.16 (2N, m), 12.29 (1 N, s).

Auxiliary Example 175

Preparation of b-ethyl-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-3-(2,2,3,3-tetrafluoropropoxy)-4,5-dihydro-1H-pyrroloyi3,2 -c|Ipyridine-2-carboxylic acid me Song shi (c;

IS

IS

E M (in) E

WITH

According to a method similar to the method given in Auxiliary Example 150, ethyl 6b-ethyl-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-3-(2,2,3,3-tetrafluoropropoxy )-4,5-dihydro-1H-pyrrole|3,2-s|Ipyridine-2-carboxylate (460 mg, 93 95) was obtained in the form of a gray powder from the compound of Auxiliary

Example 40 (382 mg, 1.00 mmol), 2,2,3,3-tetrafluoropropyltrifluoromethanesulfonate (913 mg, 3.46 mmol), cesium carbonate (391 mg, 1.20 mmol) and DMF (10 mL). The title compound (310 mg, 95 95) was obtained as a gray powder from ethyl 6b-ethyl-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-3-(2, 2,3,3-tetrafluoropropoxy)-4,5-dihydro-1H-pyrrolo|3,2-c|pyridine-2-carboxylate (348 mg, 0.70 mmol) using a method similar to that given in the Auxiliary

Examples 59. "H-NMR (300 MHz, DMSO-α) 6: 1.19 (3 N, t, U-7.3 Hz), 2.58 (2 N, k, U-7.3 Hz) , 3.86 (Z H, c), 4.70 (2H, t, U«13.1 Gu), 5.62 (2 H, c), 6.54 (1 H, c), 6.73 (1H, tt, U-52.6, 6.1 Hz), 7.56-7.66 (2H, m), 7.69-7.79 (1H, m), 8.07-8.17 (2H, m), 12.93 (1H, w s).

Auxiliary Example 176

Preparation of 3-(cyclopropylmethoxy)-6-ethyl-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo|3,2-c|Ipyridine- 2-carboxylate me. co

Their same (c) - 5. M (c)

WITH

By a procedure similar to that given in Auxiliary Example 150, the title compound (65 mg, 15 95) was prepared as a yellow powder from the compound of Auxiliary Example 40 (382 mg, 1.00 mmol), cesium carbonate (358 mg, 1.10 mmol), cyclopropyl methyl methanesulfonate (750 mg, 5.00 mmol) and DMF (10 mL). "H-NMR (300 MHz, SOS") 5: 0.29-0.36 (2N, m), 0.49-0.57 (2N, m), 1.24-1.37 (1N, m) , 1.28 (ZN, t, 9-7.3

Hu), 1.41 (ZN, t, U-7.1 Hu), 2.51 (2H, k, du-7.4 Hu, 3.88 (Z H, s), 4.10 (2 H , d, 957.2 Hz), 4.37 (2H, k, 9U71

Hz), 5.59 (2H, s), 6.19 (1H, s), 7.47-7.55 (2H, m), 7.59-7.67 (1H, m), 8.02 -8.10 (2H, m).

Auxiliary Example 177

Preparation of 3-(cyclopropylmethoxy)-6-ethyl-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo|3,2-c|Ipyridine- 2-carboxylic acid me. sleep

M. H

HU (9;

E M (c) -7

WITH

By a procedure similar to that given in Auxiliary Example 59, the title compound (112 mg, 83 95) was obtained as a colorless powder from the compound of Auxiliary Example 176 (144 mg, 0.33 mmol). "H-NMR (300 MHz, DMSO-α) 6: 0.17-0.27 (2Н, m), 0.39-0.48 (2Н, m), 1.03-1.22 (1Н, m), 1.18 (ZH, t, 9uU7, З Hz), 2.56 (2 Н, k, 9-7.3 Gu), 3.84 (З Н, s), 3.94 (2Н, d, 957.0 Hz), 5.58 (2 N, s), 6.46 (1N, s), 7.56-7.65 (2N, m), 7.69-7.77 (1N, m), 8.07-8.15 (2H, m), 12.43 (IN, w s).

Example 1

Preparation of /3-methoxy-5-(2-oxo-2-phenylethyl)-2-(piperidin-1-ylcarbonyl)thieno|3,2-c|quinolin-4(5H)-one o;

DV, with x shsh- OoMe

M (o; p:

And a solution (0.10 M, 0.600 ml, 60 μmol) of the compound of Auxiliary Example 7 in DMF was diluted with DMF (0.200 ml), and a solution (1.0 M, 0.063 ml, 63 μmol) of piperidine in DMF and a solution (0. 50 M, 0.126 ml, 63 μmol) NOVI and MU/UZSO in a 1:11 mixture in DMF. The resulting mixture was shaken at room temperature for 13 hours. To the reaction mixture were added dichloromethane (2 mL) and a saturated aqueous solution of sodium hydrogen carbonate (1 mL), and the organic layer was filtered through a Teflon filter (registered trademark), separating from the aqueous layer, and concentrated under reduced pressure.

The residue was purified by preparative HPLC to give the title compound (8.5 mg,

C1 Ob).

РХ/МС 461 (М--Н).

Example 2

Preparation of M-ethyl-M-(1-(3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno|3,2-c)quinolin-2-yl)carbonyl )pyrrolidin-3-yl)acetamide

Z o x m x U Me shsh- OMe gyi

M o 5

By a method similar to the method given in Example 1, the title compound was obtained from the compound of Auxiliary Example 7 and M-ethyl-M-pyrrolidine-33-ylacetamide.

РХ/МС 532 (М.Н).

Example C

Preparation of M-(2-(diethylamino)ethyl|-3-methoxy-M-methyl-4-oxo-5-(pyridin-2-ylmethyl)-4,5-dihydrothienoyl3,2-quinoline-2-carboxamide ditrifluoroacetate

EC

M-E

IF; uh-

M

5 Me x -- OMe

M c) ex

M 2 SEZSOZN

To a solution (0.12 M, 0.40 ml, 48 μmol) of the compound of Auxiliary Example 19 in DMF was added a solution (0.66 M, 0.10 ml, 63 μmol) of M, M-diethyl-M'-methylethane-1 ,2-diamine in DMF and a solution (0.39 M, 0.20 ml, 78 μmol) of NOVI and MU/UZSO in a 1:11 mixture in DMF. The resulting mixture was shaken at room temperature for 14 hours. To the reaction mixture, dichloromethane (2 mL) and a saturated aqueous solution of sodium bicarbonate (1 mL) were added, and the organic layer was filtered through a Teflon filter (registered trademark), separating from the aqueous layer, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (33.2 mg, 98 Vol).

РХ/МС 479 (М.Н).

Example 4

Preparation of 2-Sh14-(1,3-benzodioxol-5-ylmethyl)piperazine-1-ylcarbonyl)-3-methoxy-5-(pyridin-2-

ylmethyl)thienoic|3,2-c|quinolin-4(5H)-one ditrifluoroacetate

Shu

IF) about It

M M

2 so OMe

M (6) -x

M 2 SEASON

By a method similar to that given in Example C, the title compound was obtained from the compound of Auxiliary Example 19 and 1-(1,3-benzodioxol-5-ylmethyl)piperazine.

РХ/МС 569 (М.Н).

Example 5

Preparation of M-(2-(dimethylamino)ethyl|-3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoic|3,2-syquinoline-2-carboxamide trifluoroacetate

Me m-Mme b00/

MN

5-

And OM is 0-4 dO that | SEzZSO'N

To a solution (0.15 M, 0.40 ml, 60 μmol) of the compound of Auxiliary Example 7 in DMF was added a solution (0.66 M, 0.10 ml, 63 μmol) of M,M-dimethylethane-1,2-diamine in DMF solution (0.39 M, 0.20 ml, 78 μmol)

NEW and MUZSO in a mixture of 1:11 in DMF. The resulting mixture was shaken at room temperature for 14 hours. To the reaction mixture was added dichloromethane (2 mL) and a saturated aqueous solution of sodium hydrogen carbonate (1 mL), and the organic layer was filtered through a Teflon filter (registered trademark), separating from the aqueous layer, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (25.2 mg, 73 95).

РХ/МС 464 (М.Н).

Example 6

Preparation of trifluoroacetate 3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-M-(2-pyrrolidin-1-ylethyl)-4,5-dihydrothieno-3,2-syquinoline-2-carboxamide

IN,

SHM-- about KE

A-MN 8th grade 9-0

AND

4 SEASON

By a method similar to the method given in Example 5, the title compound was obtained from the compound of Auxiliary Example 7 and 2-pyrrolidin-1-ylethanamine.

РХ/МС 490 (М--Н).

Example 7

Preparation of M-Y3-(1H-imidazol-1-yl)propyl|-3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoyl-3,2-siquinoline-2-carboxamide trifluoroacetate -3 ny o / / khm y

With and in that volume

Zzyastmoto 0-4

DE» sh SEZSOZN

By a method similar to the method given in Example 5, the title compound was obtained from the compound of Auxiliary Example 7 and 3-(1H-imidazol-1-yl)upropan-1-amine.

РХ/МС 501 (М--Н).

Example 8

Preparation of 3-methoxy-N-(2-(1-methylpyrrolidin-2-yl)ethyl|-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoyl3,2-siquinoline-2- trifluoroacetate carboxamide 7-M, about | Me

What's up with them Y

S OomMe - M te! bO-sh and - SEZzSOzN

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 7 and 2-(1-methylpyrrolidin-2-yl)ethanamine.

РХ/МС 504 (М.Н).

Example 9

Preparation of trifluoroacetate 33-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-M-(2-piperidin-1-ylethyl)-4,5-dihydrothieno|3,2-syquinoline-2-carboxamide

BUT, (c) i-

MN

With x shsh- OMe

M o 0-0 with SEZSOZN

By a method similar to the method given in Example 5, the title compound was obtained from the compound of Auxiliary Example 7 and 2-piperidin-1-ylethanamine.

РХ/МС 504 (М.Н).

Example 10

Preparation of M-I|Z-(diethylamino)propyl|-3Z-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoic|3,2- syquinoline-2-carboxamide trifluoroacetate

IS

M o r d E 7-tn y

FO ZOomMe ih Shk is; at.

H sia | SEgzSOZN

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 7 and M,M-diethylpropane-13-diamine.

РХ/МС 506 (М--Н).

Example 11

Preparation of trifluoroacetate 3-methoxy-M-(3-morpholin-4-ylpropyl)-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoyl-3,2-quinoline-2-carboxamide

M (9; same DY,

MN h

Y a OoMe mo 0-5

WITH SEZSOZN

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 7 and 3-morpholin-4-ylpropan-1-amine.

РХ/МС 520 (М.Н).

Example 12

Preparation of 3-methoxy-N-3-(4-methylpiperazin-1-yl)propyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoyl3,2-quinoline-2-carboxamide ditrifluoroacetate

M M-M -me 9/7

MN

From what OMe

M o 0 th of 2 SEZSO»N

By a method similar to the method given in Example 5, the title compound was obtained from the compound of Auxiliary Example 7 and 3-(4-methylpiperazin-1-yl)upropan-1-amine.

РХ/МС 533 (М.Н).

Example 13

Preparation of M-(4-(diethylamino)-1-methylbutyl|-33-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoyl-3,2-siquinoline-2-carboxamide trifluoroacetate

EC

M-EI

Me o

MN

WITH

Go - OoMe

M (o) 0 with SEZSOZN

By a method similar to the method given in Example 5, the title compound was obtained from the compound of Auxiliary Example 7 and M',M'-diethylpentane-1,4-diamine.

РХ/МС 534 (М.Н).

Example 14

Preparation of M-(1-benzylpyrrolidin-3-yl)-3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoyl3,2-quinoline-2-carboxamide trifluoroacetate es o -

MN shcha

So om

FI e ry -. schocho o

F shooi SEzZSOZN

By a method similar to the method given in Example 5, the title compound was obtained from the compound of Auxiliary Example 7 and 1-benzylpyrrolidin-3-amine.

РХ/МС 552 (М.Н).

Example 15

Preparation of trifluoroacetate M-(1-benzylpiperidin-4-yl)-3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoyl-3,2-siquinoline-2-carboxamide

M sh schi,

MN

With oh p OMe

M o 0-0

WITH SEZSOZN

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 7 and 1-benzylpiperidine-4-amine.

РХ/МС 566 (М.Н).

Example 16

Preparation of 3-methoxy-N-methyl-N-(1-methylpyrrolidin-3-yl)-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoyl-3,2-siquinoline-2-carboxamide trifluoroacetate

- Me

M o

M x Me so a OoMe

MI c) 0-4

WITH SEZSOZN

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 7 and M, 1-dimethylpyrrolidine-3-amine.

РХ/МС 490 (М--Н).

Example 17

Preparation of trifluoroacetate trifluoroacetate Me what

With x still OMe

M o) 0th from SEZSOZN

By a method similar to the method given in Example 5, the title compound was obtained from the compound of Auxiliary Example 7 and 1-methyl-1,4-diazepane.

РХ/МС 490 (М--Н).

Example 18

Preparation of trifluoroacetate 2-((4-ethylpiperazin-1-yl/ucarbonyl|-3-methoxy-5-(2-oxo-2-phenylethyl)thieno|3,2-c)quinolin-4(5H)-one KU

M M-E 2 and V OoMe

M (c) 0-4

From SEzSOZNNn

By a method similar to the method given in Example 5, the title compound was obtained from the compound of Auxiliary Example 7 and 1-ethylpiperazine.

РХ/МС 490 (М--Н).

Example 19

Preparation of trifluoroacetate M-(2-(diethylamino)ethyl|-3-methoxy-M-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoyl-3,2-siquinoline-2-carboxamide

EC

M-E (F), K-

M. x Me i. - oMe

M F) 0-2

From SEZSOon

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 7 and M,M-diethyl-M'-methylethane-1,2-diamine.

РХ/МС 506 (М--Н).

Example 20

Preparation of 3-methoxy-5-(2-oxo-2-phenylethyl)-2-(25)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)iccarbonyluthieno|3,2-c)quinoline-4( 5H)-one trifluoroacetate

I

7 o'clock

Di

WITH

Go - In OoMe

Mo; 0th

With SEZSO»N

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 7 and 1-(25)-pyrrolidin-2-ylmethyl|pyrrolidine.

РХ/МС 530 (М--Н).

Example 21

Preparation of trifluoroacetate 3-methoxy-5-(2-oxo-2-phenylethyl)-2-(4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl|hyeno-3,2-sequinolin-4(5H)-one. t

M DV

With x and i

SG OoMe

With tm o o.

SCHI SRaSO»Nn

By a method similar to the method given in Example 5, the title compound was obtained from the compound of Auxiliary Example 7 and 4-pyrrolidin-1-ylpiperidine.

РХ/МС 530 (МН).

Example 22

Preparation of M-(2-cyanoethyl)-3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-M-(pyridin-3-ylmethyl)-4,5-dihydrothienoyl3,2-siquinoline-2 -trifluoroacetate carboxamide

SM

7 o)

Zh-Mosya-M a,

Goh U in

M (o) o shk sho sh SEgZSOzN

By a method similar to the method given in Example 5, the title compound was obtained from the compound of Auxiliary Example 7 and 3-pyridin-3-ylmethyl)amino|propanenitrile.

РХ/МС 537 (М.Н).

Example 23

Preparation of 2-C4-(1,3-benzodioxol-5-ylmethyl)piperazin-1-ylcarbonyl)-3-methoxy-5-(2-oxo-2-phenylethyl)thienoyl3,2-c|quinolin-4(5H) -on trifluoroacetate shk o --

Zm M

Ky

With oh still OomMme oh Moto what

S SsEZSO»Nn

By a method similar to the method given in Example 5, the title compound was obtained from the compound of Auxiliary Example 7 and 1-(1,3-benzodioxol-5-ylmethyl)piperazine.

РХ/МС 596 (INN).

Example 24

Preparation of M-(2-(diethylamino)ethyl|-3-(2-ethoxyethoxy)-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoyl-3,2-siquinoline-2-carboxamide trifluoroacetate

EE

M-EI (c), Ж-

MN

With oh t and

M ) oi 0

WITH SEASON

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 21 and M,M-diethylethane-1 2-diamine.

РХ/МС 550 (МН).

Example 25

Preparation of M, M-diethyl-3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno|3,2-c)quinoline-2-carboxamide by EE

M, x EI with OoMe

M) ri

To a solution of the compound of Auxiliary Example 7 (130 mg, 0.33 mmol), diethylamine (36 mg, 0.49 mmol) and

To NOVI (67 mg, 0.49 mmol) in DMF (4 mL) was added MUZSO (94 mg, 0.49 mmol) while cooling on ice and the mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The extracts were combined, washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluate; ethyl acetate) and the resulting oil was recrystallized from ethyl acetate-diethyl ether to give the title compound (104 mg, 70 95) as white crystals. "H-NMR (300 MHz, DMSO-α) 6: 1.15 (6H, t, 9-71 Hz), 3.39-3.50 (4H, m), 3.87 (ZH, s), 5.98 (2H, s), 7.33 (1H, t, U-7.5 Hz), 7.48 (IN, d, U-7.8 Gu), 7.56 (1H, td, U -8.7, 1.2 Gu), 7.64 (2H, t, 9-7.5 Hz), 7.75 (1H, d, 4-7, Hz), 7.96 (1H, dd, 9U-7.8, 1.2 Hz), 8.18 (2H, d, U-7.5 Hz).

Example 26

Preparation of 3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-M-phenyl-4-5-dihydrothieno|3,2-s|quinoline-2-carboxamide (8) B,

And what

In OMe

I

M (9) ri

By a procedure similar to that of Example 25, the title compound (163 mg, 63 95) was obtained as pale orange crystals from the compound of Auxiliary Example 7 (200 mg, 0.51 mmol) and aniline (48 μl, 0 .51 mmol). "H-NMR (300 MHz, DMSO-α) 5: 4.15 (ZH, s), 6.02 (2H, s), 7.12-7.21 (1H, m), 7.32-7 .44 (ZN, m), 7.48-7.55 (1Н, m), 7.56-7.70 (ZN, m), 7.71-7.82 (ZN, m), 8.09 (1H, dd, 9-7.9, 1.3 Hu), 8.14-8.24 (2H, m), 9.74 (1H, s).

Example 27

Preparation of 3-methoxy-M-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-M-(2-oxo-2-pyrrolidin-1-ylethyl)-4,5-dihydrothienoi3,2-syquinoline -2-carboxamide

TYA Fr

M, Fr

X Me with OoMe

More

A mixture of a solution of the compound of Example 120 (400 mg, 0.81 mmol) and a 2M aqueous solution of sodium hydroxide (10 mL) in THF (10 mL)-ethanol (5 mL) was stirred at room temperature for 2 hours.

The reaction mixture was neutralized with 2M hydrochloric acid (10 ml) and concentrated under reduced pressure. The residue was partitioned between brine and ethyl acetate, and the aqueous phase was extracted with ethyl acetate. The organic phase was combined, dried over magnesium sulfate and concentrated under reduced pressure to give M-(3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoi3,2-syquinoline- 2-ylcarbonyl-M-methylglycine (380 mg, 100 95) as a white solid.

The title compound (84 mg, 40 95) was obtained as white crystals from similarly prepared M-3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoi|Z, 2-c|quinolin-2-yl|carbonyl)-N-methylglycine (190 mg, 0.41 mmol) and pyrrolidine (44 mg, 0.61 mmol) using a method similar to that given in Example 25." H-NMR (300 MHz, SOS") 6: 1.75-2.05 (4H, m), 3.20 (1H, s), 3.27 (2H, s), 3.45-3.56 (4H, m), 4.01 (1H, s), 4.13 (2H, s), 4.23 (0.6H, w s), 4.29 (1.4H, s), 5.86 (2H, s), 7.03 (1H, d, U-8.4 Hz), 7.23-7.28 (1H, m), 7.45 (IN, t, U-8.0 Hz) , 7.55 (2H, t, 9-7.5 Hu), 7.67 (1H, t, U-7.2 Hz), 7.82 (1H, dd, 9-81, 1.2 Hu) , 8.10-8.12 (2H,

M).

Example 28

Preparation of 3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-M-(2-pyrrolidin-1-ylethyl)-4,5-dihydrothieno|3,2-syquinoline-2-carboxamide xi ( F) her daughter OMe

M (c) ri

By a method similar to that given in Example 25, the title compound (1.54 g, 67 95) was obtained as white crystals from the compound of Auxiliary Example 7 (1.85 g, 4.69 mmol) and 1-(2 -aminoethyl)pyrrolidine (642 mg, 5.63 mmol). "H-NMR (300 MHz, DMSO-av) 5: 1.72 (4H, w s), 2.45-2.60 (4H, w), 2.64 (2H, t, U-6.3 Hz), 3.44 (2H, t, 9-5.9 Hz), 4.01 (ЗН, s), 6.00 (2H, s), 7.35 (1TN, t, U-7.8 Gu), 7.49 (1TN, d, U-8.1 Hz), 7.55-7.67 (ZN, m), 7.70 (IN, t, U-7.5 Hz), 8, 05 (1H, dd, 9U-8.1, 1.5 Hz), 8.16-8.19 (ZH, m).

Example 29

Preparation of /- M-(2-(diethylamino)-2-oxoethyl|-3-methoxy-M-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-

of dihydrothienoi3,2-sequinoline-2-carboxamide

MES, o i h

M o x Me s OoMe

M o)

H

By a procedure similar to that of Example 25, the title compound (124 mg, 5895) was obtained as white crystals from M-(3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)- 4,5-dihydrothienoyl3,2-syquinoline-2-ylcarbonyl-M-methylglycine (190 mg, 0.41 mmol), obtained in Example 27, and diethylamine (45 mg, 0.61 mmol). "H-NMR (300 MHz, SOS") 6: 1.05-1.31 (6N, m), 3.18 (1.2N, s), 3.26 (1.8N, s), 3.34-3.47 ( AN, m), 4.01 (1.2N, s), 4.10 (1.8N, s), 4.30 (0.8N, s), 4.36 (1.2N, s), 5 .85 (2H, s), 7.03 (1H, d, U-8.4 Hz), 7.23-7.28 (1H, m), 7.46 (1H, t, 9-74 Hz) . ,11 (2H, d,

U-7.2 Hz).

Example 30

Preparation of 3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-M-(2-pyrrolidin-1-ylethyl)-4,5-dihydrothieno-3,2-syquinoline-2-carboxamide hydrochloride

And no

M her shchi with OoMe

M (in) r

To a solution of the compound of Example 28 (200 mg, 0.41 mmol) in ethyl acetate (25 ml) was added a 4M solution of hydrochloride in ethyl acetate (0.11 ml). The resulting residue was collected by filtration, washed with ethyl acetate and dried under reduced pressure to give the title compound (162 mg, 75 95) as a white powder. "H-NMR (300 MHz, DMSO-α) 5: 1.77-2.10 (AN, m), 2.95-3.10 (2H, w), 3.29-3.40 (2H, m), 3.55-3.75 (4H, m), 4.07 (ZH, s), 6.00 (2H, s), 7.36 (1H, t, 9U-7.4 Gu), 7.51 (1IN, d, U-8.4 Hz), 7.57-7.67 (ЗН, m), 7.78 (1Н, t, 3-74 Hz), 8.06 (1Н, dd , U9-7.8, 1.2 Hz), 8.16-8.19 (2H, m), 8.31 (1H, t, U-6.0 Hz), 10.33 (IN, w s).

Example 31

Preparation of 3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-M-(2-pyrrolidin-1-ylethyl)-4,5-dihydrothienoic 3,2-syquinoline-2-carboxamide methanesulfonate

And (F) i-

M MezO,N schi s OMe

M (c) ri

To a solution of the compound of Example 28 (200 mg, 0.41 mmol) in ethyl acetate (25 ml) was added a solution of methanesulfonic acid (39 mg, 0.41 mmol) in ethyl acetate (5 ml). The resulting residue was collected by filtration, washed with ethyl acetate and dried under reduced pressure to give the title compound (197 mg, 82 95) as a white powder. "H-NMR (300 MHz, DMSO-α) 6: 1.65-2.10 (4Н, m), 2.30 (ЗН, с), 3.00-3.20 (2Н, w), 3 ,35-3,45 (2H, w),

З3.60-3.75 (4Н, m), 4.06 (ЗН, с), 6.00 (2Н, с), 7.36 (IN, t, 957.2 Gu), 7.51 (1Н , d, U-8.4 Hz), 7.57-7.67 (ZH, m), 7.78 (1H, t, 9U-7.5 Hz), 8.06 (1H, dd, 9U- 7.8, 1.2 Hz), 8.16-8.19 (2H, m), 8.29 (1H, t, U-5.9 Hz), 9.30-9.45 (IN, w ).

Example 32

Preparation of M-(2-hydroxyethyl)-3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno|3,2- syquinoline-2-carboxamide

On (0; --- xx mi n fii se OMe shi -

M (in) 0-4

It's me

By a procedure similar to that of Example 25, the title compound (65.8 mg, 67 95) was obtained as a white powder from the compound of Auxiliary Example 7 (89.0 mg, 0.226 mmol) and 2-aminoethanol (16, 3 μL, 0.271 mmol). "H-NMR (300 MHz, DMSO-α) 6: 3.40-3.46 (2H, m), 3.54-3.59 (2H, m), 4.03 (ZH, s), 4 .87 (1H, t, 9-5.3

Hu), 5.99 (2Н, с), 7.32-7.38 (1Н, m), 7.48-7.67 (4Н, m), 7.74-7.79 (1Н, m) , 8.00-8.06 (2H, m), 8.16-8.19 (2H,

M).

Example 33

Preparation of M-cyclopropyl-3-methoxy-5-methyl-4-oxo-4,5-dihydrothieno|3,2-c)quinoline-2-carboxamide o /

M

R with OMe

M (c);

Me

By a method similar to that given in Example 1, the title compound was prepared from the compound of Auxiliary Example 84 and cyclopropanamine.

РХ/МС 329 (МН).

Example 34

Preparation of /- M-(2-(diethylamino)ethyl|-3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoic|3,2- sequinoline-2-carboxamide

MES

(F) -i-

M

R sp OMe

M (F) ri

By a procedure similar to that of Example 25, the title compound (500 mg, 80 95) was obtained as white crystals from the compound of Auxiliary Example 7 (500 mg, 1.27 mmol) and M,M-diethylethylenediamine (220 mg , 1.90 mmol). "H-NMR (300 MHz, DMSO-av) 6: 1.00 (6H, t, 9U-7.1 Hz), 2.50-2.62 (6H, m), 3.37-3.42 (2H, m), 4.03 (ZH, s), 6.00 (2H, s), 7.35 (1H, t, 9U-7.4 Gu), 7.49 (1H, d, U- 8.4 Hz), 7.55-7.67 (ZH, m), 7.77 (1H, t, 9-7.5 Gu), 8.05 (IN, dd, 9U-7.8, 1 .5 Gu), 8.12 (1H, t, 9-51 Hz), 8.16-8.19 (2H, m).

Example 35

Preparation of M-benzyl-33-methoxy-5-methyl-4-oxo-4,5-dihydrothienoi3,2-quinoline-2-carboxamide

M

R xx OMe them (in);

Me

By a method similar to that given in Example 1, the title compound was obtained from the compound of Auxiliary Example 84 and 1-phenylmethanamine.

РХ/МС 379 (INN).

Example 36

Preparation of 3-methoxy-5-methyl-4-oxo-M-(3-phenylpropyl)-4,5-dihydrothienoic acid 3,2-c|quinoline-2-carboxamide nd I,

M

R xx OMe

M (c);

Me

By a method similar to that given in Example 1, the title compound was obtained from the compound of Auxiliary Example 84 and 3-phenylpropan-1-amine.

РХ/МС 407 (МН).

Example 37

Preparation of 3-methoxy-M-(2-methoxyethyl)-5-methyl-4-oxo-4,5-dihydrothieno|3,2-c|quinoline-2-carboxamide

ОМе (in) ,Н-

M

R xx OMe

M (c);

Me

By a method similar to that given in Example 1, the title compound was obtained from the compound of Auxiliary Example 84 and 2-methoxyethanamine.

РХ/МС 347 (INN).

Example 38

Preparation of 3-methoxy-5-methyl-4-oxo-M-(tetrahydrofuran-2-ylmethyl)-4,5-dihydrothieno-3,2-c|quinolin-2-carboxamide 8-3

M (F) z hu OMe them (F)

Me

By a method similar to that given in Example 1, the title compound was obtained from the compound of Auxiliary Example 84 and 1-(tetrahydrofuran-2-yl)methanamine.

РХ/МС 373 (INN).

Example 39

Preparation of 3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-M-(2-pyrrolidin-1-ylethyl)-4,5-dihydrofuro|3,2- syquinoline-2-carboxamide ( F) y-y-ryh / N

AND; ra s OoMe

clear (6)

She and y

By a procedure similar to that of Example 25, the title compound (125 mg, 66 95) was obtained as a white powder from the compound of Auxiliary Example 24 (150 mg, 0.397 mmol) and 1-(2-aminoethyl)pyrrolidine (65.4 μl, 0.516 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.69-1.73 (4H, m), 2.49-2.51 (AN, m), 2.61 (2H, t, U- 6.6 Hz), 3.40-3.46 (2H, m), 4.15 (ZH, s), 6.00 (2H, s), 7.43 (1H, t, 9-81 Gu) , 7.54 (1H, d, uU-8.4 Hz), 7.60-7.67 (ZH, m), 7.74-7.79 (IN, m), 8.06 (1H, t , 9U-8.6 Hz), 8.15-8.19 (ZN, m).

Example 40

Preparation of 3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-M-(2-pyrrolidin-1-ylethyl)-4,5-dihydro-1H-pyrrolyl3,2-s |quinoline-2-carboxamide t

Mo --

Me, Shi:

IM i o ah Me

My M o o t r

AND

By a procedure similar to that of Example 25, the title compound (145 mg, 78 95) was obtained as a white powder from the compound of Auxiliary Example 28 (150 mg, 0.384 mmol) and 1-(2-aminoethyl)pyrrolidine (63 .3 μl, 0.499 mmol). "H-NMR (300 MHz, DMSOO-av) 6: 1.65-1.75 (AN, m), 2.48-2.55 (AN, m), 2.62 (2Н, t, 9- 6.2 Hz), 3.39-3.45 (2H, m), 3.97 (ZH, s), 4.37 (ZH, s), 5.97 (2H, s), 7.29- 7.39 (2H, m), 7.45-7.50 (1H, m), 7.61-7.66 (2H, m), 7.73-7.78 (IN, m), 8, 16-8.18 (ZH, m), 8.39 (1H, dd, 9-81, 1.2 Hz).

Example 41

Preparation of 5-(cyclopropylmethyl)-M-(2-(diethylamino)ethyl|-3-methoxy-M-methyl-4-oxo-4,5-dihydrothienoyl3,2-syquinoline-2-carboxamide

EC

M-E (8) -th-

M

X Me r OoMe -y M o

To a solution of the compound of Example 121 (400 mg, 1.03 mmol) in DMF (5 mL) was added sodium hydride (60 Fo in oil, 45.4 mg, 1.14 mmol) while cooling on ice, and the mixture was stirred for 15 minutes. Cyclopropyl methyl bromide (120 μl, 1.24 mmol) was added to the resulting mixture while cooling on ice, and the mixture was stirred for 15 hours. The reaction mixture was added to water and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on amino silica gel (eluate; ethyl acetate/hexane-3/7) to give the title compound (320 mg, 70 90) as a colorless oil. "H-NMR (300 MHz, DMSO-α) 5: 0.45-0.50 (4H, m), 0.70-1.05 (6H, w), 1.23-1.31 (1H, m), 2.25-2.70 (6H, w), 3.06 (ZH, s), 3.40-3.60 (2H, w)y, 3.89 (ZH, s), 4, 27 (2H, d, U-6.9 Hz), 7.30-7.35 (1H, m), 7.62-7.68 (1H, m), 7.76 (IN, d, 9U- 8.4 Hz), 7.91 (1H, dd, U-7,8,1,2 Gu).

Example 42

Preparation of M-(2-(diethylamino)ethyl|-3-methoxy-M-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrofuro!|3,2-c|quinoline -2-carboxamide

ЕЙ and m-ЭБЙ о - хм ж о х ме - Z "OomMe shck t

And oh)

H

By a procedure similar to that of Example 25, the title compound (130 mg, 80 95) was obtained as a colorless oil from the compound of Auxiliary Example 24 (130 mg, 0.344 mmol) and M,M-diethyl-M'-methylethylenediamine (72.3 μl, 0.477 mmol). "H-NMR (300 MHz, DMSO-α) 6: 0.75-0.90 (ZH, w), 0.90-1.05 (ZH, w), 2.25-2.40 (2H, w), 2.45-2.70 (4H, shu, 2.95-3.30 (ZH, w), 3.52 (2H, t, U-6.5 Hz), 4.04 (ZH, s), 5.99 (2H, s), 7.37-7.42 (1H, m), 7.52 (1H, d, 9-8.7

Hz), 7.57-7.67 (ZH, m), 7.74-7.79 (1H, m), 8.04 (1H, d, 9-7.5 Hz), 8.16-8 ,19 (2H, m).

Example 43

Preparation of // 3-ethoxy-4-oxo-5-(2-oxo-2-phenylethyl)-M-(2-pyrrolidin-1-ylethyl)-4,5-dihydrothienoi3,2-syquinoline-2-carboxamide c ( c) -y-yy; also Fk

M IF) ri

By a procedure similar to that of Example 25, the title compound (126 mg, 67 95) was obtained as white crystals from the compound of Auxiliary Example 9 (150 mg, 0.37 mmol) and 1-(2-aminoethyl)pyrrolidine (63 mg, 0.55 mmol). "H-NMR (300 MHz, DMSO-av) 5: 1.39 (ZH, t, 9U-7.0 Hu), 1.72 (4H, w s), 2.40-2.60 (4H, w), 2.63 (2H, t, 9-6.0 Hz), 3.40-3.47 (2H, m), 4.31 (2H, k, 9-7.0 Hz), 5, 99 (2H, s), 7.35 (1H, t, 9-7.8 Hz), 7.48 (1H, d, U-8.4

Hu), 7.56 (1H, dd, 9U-7.2, 1.5 Hz), 7.64 (2H, t, 9U-8.4 Hu), 7.77 (1H, t, U-7 .2 Hz), 8.05 (1H, dd, 9-81, 1.5 Hz), 8.10 (1H, w t), 8.16-8.19 (2H, m).

Example 44

Preparation of M-(2-(diethylamino)ethyl|-M-ethyl-3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoyl-3,2-syquinoline-2-carboxamide

ME o,iЯ-

M,

I'm sorry

Mm'sSo 5

By a procedure similar to that of Example 25, the title compound (150 mg, 56 95) was obtained as white crystals from the compound of Auxiliary Example 7 (200 mg, 0.51 mmol) and M, M, M'-- triethylethylenediamine (110 mg, 0.76 mmol). "H-NMR (300 MHz, DMSO-α) 5: 0.70-1.10 (6H, w), 1.14 (ZH, w t), 2.20-2.70 (6H, w), 3.40-3.60 (4H, w), 3.87 (ZH, s), 5.98 (2H, s), 7.33 (1H, t, 9-7.5 Gu), 7.47 (1H, d, 9-81 Hz), 7.55 (1H, td, 9U-7.8, 1.5 Hz), 7.64 (2H, t, U-7.5 Hz), 7.77 (1H, t, U-7.5 Hz), 7.95 (1H, dd, U-7.8, 1.5 Hz), 8.16-8.19 (2H, m).

Example 45

Preparation of M-(2-(diethylamino)ethyl|-3-ethoxy-M-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoyl-3,2-siquinoline-2-carboxamide hydrochloride

OIE about

M, in x Me s (Fi

NSI

M F) ri

To a solution of the compound of Auxiliary Example 9 (150 mg, 0.37 mmol), M,M-diethyl-M'-methylethylenediamine (72 mg, 0.55 mmol) and NOVI (74 mg, 0.55 mmol) in DMF (5 ml) was added MUZSO (105 mg, 0.55 mmol) while cooling on ice, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The extracts were combined, washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluate; ethyl acetate/hexane-1/1) to give a non-crystalline white solid (180 mgHg).

To a solution of a white non-crystalline solid (180 mg) in ethyl acetate (5 ml) was added

AM solution of hydrochloride in ethyl acetate (0.1 ml). The resulting residue was collected by filtration, washed with ethyl acetate and dried under reduced pressure to give the title compound (173 mg, 83 95) as a white powder. "H-NMR (300 MHz, DMSO- av) 5: 1.15-1.35 (9H, m), 3.12-3.40 (9H, w), 3.84 (2H, t, U- 7.2 Gu), 4.14 (2H, k, 9U-7.0 Hz), 5.99 (2H, s), 7.35 (1H, t, 9U-7.5 Hz), 7.49 (1H, d, 9-81 Hz), 7.55-7.67 (ZH, m), 7.75-7.80 (1H, m), 7.98 (1H, dd, 9U-8.1 , 1.5 Hz), 8.16-8.19 (2H, m), 9.85-10.10 (1H, w).

Example 46

Preparation of M-(2-(diethylamino)ethyl|-3-methoxy-M-(1-methylethyl)-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoi3,2-siquinoline- 2-carboxamide hydrochloride

Me o 00)-Me

M

X; pcs OMe ME

M' ns re

By a procedure similar to that of Example 45, the title compound (164 mg, 56 96) was obtained as a white powder from the compound of Auxiliary Example 7 (200 mg, 0.51 mmol) and M,M-diethyl-M' -isopropylethylenediamine (120 mg, 0.76 mmol). "H-NMR (300 MHz, DMSOO-av) 6: 1.20-1.35 (12Н, m), 3.15-3.40 (6Н, w), 3.65-3.80 (2Н, m), 3.89 (ZH, s), 4.10-4.30 (IN, w), 5.99 (2H, s), 7.33 (1H, t, 9-7.5 Hz), 7.49-7.67 (4H, m), 7.77 (1H, t, 9U-7.5 Hz), 7.97 (1H, dd, 9-7.2,1.2 Gu), 8 ,16-8.19 (2H, m), 9.95-10.10 (1H, w).

Example 47

Preparation of M-(1-ethylpropyl)-3-methoxy-5-methyl-4-oxo-4,5-dihydrothieno|3,2-c|quinoline-2-carboxamide

KE at 00A-E

M j xx OMe

M (6)

Me

By a method similar to the method given in Example 1, the title compound was obtained from the compound of Auxiliary Example 84 and pentan-3-amine.

РХ/МС 359 (М.Н).

Example 48

Preparation of M-(2-(diethylamino)ethyl|-3-methoxy-5-(4-methoxybenzyl)-M-methyl-4-oxo-4,5-dihydrothienoyl3,2-siquinoline-2-carboxamide hydrochloride

Eh

IAE b0/-

M, there is Me x sh-- OoMe

M o gu Ne meo

By a method similar to the method given in Example 25, M-(2-(diethylamino)ethyl|-3-methoxy-5-(4-methoxybenzyl)-M-methyl-4-oxo-4,5-dihydrothienoIII3,2- c|quinoline-2-carboxamide (4.90 g, 85 95) was obtained as a colorless oil from the compound of Auxiliary Example 13 (4.50 g, 11.4 mmol) and M,

of M-diethyl-M'-methylethylenediamine (2.40 mL, 14.8 mmol).

The title compound (490 mg, 91 95) was obtained as a white powder from the thus obtained M-(2-(diethylamino)ethyl|-3-methoxy-5-(4-methoxybenzyl)-M-methyl-4-oxo -4,5- dihydrothienoyl3,2-quinoline-2-carboxamide (500 mg, 0.985 mmol) using a method similar to that given in Example 30. "H-NMR (300 MHz, DMSO-α) 6:1, 15-1.35 (6H, w), 3.13 (ЗН, с), 3.10-3.40 (6Н, w), 3.70 (ЗН, с), 3.87 (2Н, t, U-6.6 Hz), 3.96 (ZH, s), 5.52 (2H, s), 6.87 (2H, d, 9U-8.6 Hz), 7.20 (2H, d, U-8.6 Hz), 7.30 (1H, t, 9U-7.2

Hz), 7.49-7.58 (2H, m), 7.92 (1H, d, U-7.8 Gy), 10.55 (1H, s).

Example 49

Preparation of M-(2-(diethylamino)ethyl|-3-methoxy-M-methyl-4-oxo-5-(2-phenylethyl)-4,5-dihydrothienoic|3,2-syquinoline-2-carboxamide

Hey x

M-E (o) i-

M,

Me x s OMe t

By a procedure similar to that of Example 41, the title compound (45.1 mg, 28 95) was obtained as a colorless oil from the compound of Example 121 (125 mg, 0.323 mmol) and (2-bromomethyl)benzene (53, 5 μL, 0.387 mmol). "H-NMR (300 MHz, DMSO-α) 6: 0.75-1.05 (6H, w), 2.25-2.70 (6H, w), 2.92-2.97 (2H, m), 3.05 (ZH, s), 3.40-3.55 (2H, shu, 3.88 (ZH, s), 4.50 (2H, t, 9U-6.5 Hz), 7 ,20-7.26 (1H, m), 7.30-7.36 (5H, m), 7.63-7.75 (2H, m), 7.92 (1H, dd, U-7, 8, 1.5 Gu).

Example 50

Preparation of M-(2-(diethylamino)ethyl|-5-(3,3-dimethyl-2-oxobutyl)-3-methoxy-M-methyl-4-oxo-4,5-dihydrothienoi3,2-syquinoline-2- carboxamide

Eh

M-EI o ,-

M,

X Me is still OMe

M IF) for

Me A

Me

By a procedure similar to that of Example 41, the title compound (45.1 mg, 28 95) was obtained as a colorless oil from the compound of Example 121 (125 mg, 0.323 mmol) and 1-bromo-3,3-dimethylbutane -2-one (57.9 μL, 0.441 mmol). "H-NMR (300 MHz, DMSO-av) 5: 0.70-1.10 (6H, w), 1.30 (9H, s), 2.20-2.40 (6H, w), 3 .06 (ЗН, s), 3.40-3.60 (2Н, w), 3.87 (ЗН, с), 5.47 (2Н, с), 7.28-7.34 (2Н, m ), 7.55-7.61 (1H, m), 7.92 (1H, dd, 9U-7.8, 1.2 Hz).

Example 51

Preparation of M-(2-(diethylamino)ethyl|-3-methoxy-M-methyl-4-oxo-5-(2-phenoxyethyl)-4,5-dihydrothienoi3,2-syquinoline-2-carboxamide

ЕЙ h

IAE b00j-

M

5 Me x so OMme 7

WITH

By a procedure similar to that of Example 41, the title compound (75.1 mg, 43 95) was obtained as a colorless oil from the compound of Example 121 (135 mg, 0.348 mmol) and (2-bromoethoxy)benzene (105 mg , 0.522 mmol). "H-NMR (300 MHz, DMSO-av) 6: 0.70-1.10 (6H, w), 2.20-2.70 (6H, w), 3.05 (ZH, s), 3 ,40-3.60 (2H, w), 3.91 (ZH, s), 4.30 (2H, t, 9U-5.9 Gu), 4.73 (2H, t, U-5.9 Hz), 6.88-6.93 (ZH, m), 7.22-7.36 (ZH, m), 7.65 (1H, t, 3-8.0 Hz), 7.83 (1H , d, U9-8.7 Hz), 7.91 (1H, d, 9-7.8 Hz).

Example 52

Preparation of /- M-(2-(diethylamino)ethyl|-3-methoxy-M-methyl-4-oxo-5-(2-oxo-2-(phenylamino)ethyl|-4,5-dihydrothienoi3,2-siquinoline) -2-carboxamide hydrochloride

Eh

M--EYI would---

M x me o --E

M o z

NS

I

To a solution of the compound of Example 122 (150 mg, 0.336 mmol), aniline (39.8 mg, 0.437 mmol) and NOVI (68.2 mg, 0.505 mmol) in DMF (3 mL) was added UUZSO (96.8 mg, 0.505 mmol ) while cooling on ice and the mixture was stirred at room temperature for 15 hours. The reaction mixture was diluted with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The extracts were combined, washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on amino silica gel (eluate; ethyl acetate/hexane-1/1), obtaining M-(2-(diethylamino)ethyl|-3-methoxy-M-methyl-4-oxo-5-(2-oxo- 2-(Phenylamino)ethyl|-4,5-dihydrothieno|3,2-c|quinoline-2-carboxamide in the form of a colorless oil.

The title compound (65.2 mg, 35 95) was obtained as a white powder from the thus obtained /M-(2-(diethylamino)ethyl|-3-methoxy-M-methyl-4-oxo-5-(2 -oxo-2-(phenylamino)ethyl|-4,5-dihydrothienoyl-3,2-quinoline-2-carboxamide using a method similar to that described in Example

ZO. "H-NMR (300 MHz, DMSO-α) 6: 1.10-1.35 (6H, w), 3.12 (ZH, s), 3.15-3.40 (6H, w), 3 .75-3.90 (2H, w), 3.92 (ZH, s), 5.22 (2H, s), 7.07 (1H, t, U-7.5 Hz), 7.29- 7.38 (ZH, m), 7.53-7.66 (4H, m), 7.96 (1H, dd, 9-7.5, 1.4 Gu), 9.76 (1H, s) , 10.51 (1Н, с).

Example 53

Preparation of ethyl 1(2-C2-(diethylamino)ethyl|(methyl)carbamoyl)-33-methoxy-4-oxothieno|3,2-c)quinolin-5(4H)-yl|acetate

EE h

M-E b

M x 5 x Mesh oMme -

Y F)

OST

By a procedure similar to that of Example 41, the title compound (680 mg, 83 95) was obtained as a colorless oil from the compound of Example 121 (670 mg, 1.73 mmol) and ethyl bromoacetate (229 μl, 2.08 mmol ). "H-NMR (300 MHz, DMSOO-av) 5: 0.70-1.10 (6H, w), 1.23 (ZH, t, 9-7.1 Hz), 2.25-2.70 (6Н, m), 3.06 (ЗН, с), 3.40-3.60 (2Н, ш)y, 3.89 (ЗН, с), 4.18 (2Н, k, 9У-7, 1 Gu), 5.16 (2H, s), 7.34 (1H, t, 9U-7.7 Hz), 7.51 (IN, d, 9U-8.1 Hz), 7.61 (1H , t, U-8.1 Gu), 7.94 (1H, d, 9-7.7 Hz).

Example 54

Preparation of 3-methoxy-5-methyl-4-oxo-M-prop-2-yn-1-yl-4,5-dihydrothieno|3,2-c)quinoline-2-carboxamide

Go) у-н4

M

R xx OMe

M (c);

Me

By a method similar to that given in Example 1, the title compound was obtained from the compound of Auxiliary Example 84 and prop-2-yn-1-amine.

РХ/МС 327 (INN).

Example 55

Preparation of M-(2-(dimethylamino)ethyl|-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrroloyi3,2-s| quinoline-2-carboxamide

Me,

M-Me at 00/- me, i

Shk p OMe

M (9)

WITH

By a procedure similar to that of Example 25, the title compound (65.0 mg, 61 95) was obtained as a white powder from the compound of Auxiliary Example 28 (90.0 mg, 0.231 mmol) and M,M-dimethylethylenediamine ( 25.2 μL, 0.300 mmol). "H-NMR (300 MHz, DMSO-α) 6: 2.22 (6H, s), 2.44 (2H, t, U-6.2 Hz), 3.37-3.43 (2H, m ), 3.98 (ZH, s), 4.38 (ZH, s), 5.97 (2H, s), 7.29-7.39 (2H, m), 7.45-7.51 ( 1H, m), 7.63 (2H, t, 9-7.7 Hz), 7.73-7.79 (1H, m), 8.11-8.19 (ZH, m), 8.38 (1H, dd, U-8.4, 1.2 Hz).

Example 56

Preparation of /- M-(2-(diethylamino)ethyl|-3-methoxy-M, 1-dimethyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolyl3, 2-c|quinoline-2-carboxamide hydrochloride

ЕЙ h

M-EI 000J-me, M

M x Me still OoMe

M o and NSI

According to a method similar to the method given in Example 25, M-(2-(diethylamino)ethyl|-3-methoxy-

M, 1-dimethyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo|3,2-c)quinoline-2-carboxamide was obtained as a colorless oil from compounds of Auxiliary Example 28 (90.0 mg, 0.231 mmol) and

M, M-diethyl-M'-methylethylenediamine (48.6 μL, 0.300 mmol).

The title compound (75.1 mg, 60 95) was obtained as a white powder from thus obtained /M-(2-(diethylamino)ethyl|-3-methoxy-M,1-dimethyl-4-oxo-5- (2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolyl3,2-c|quinoline-2-carboxamide using a method similar to that described in

Examples 30. "H-NMR (300 MHz, DMSO-α) 6: 1.15-1.31 (6H, w), 2.95-3.40 (9H, w), 3.80-3.95 (5Н, m), 4.03 (ЗН, с), 5.98 (2Н, с), 7.29-7.50 (ЗН, m), 7.64 (2Н, t, 9У-7.5 Hz), 7.73-7.79 (1H, m), 8.16-8.19 (2H, m), 8.34 (1H, dd, y-8.3, 1.1 Gu), 9 ,80-10,15 (1H, w).

Example 57

Preparation of IM-(2-(3,4-dimethoxyphenyl)ethyl|-3-methoxy-5-methyl-4-oxo-4,5-dihydrothienoic|3,2-syquinoline-2-carboxamide

Ome

Ohm c)

M j xx OMe

M (c)

Me

By a method similar to that given in Example 1, the title compound was obtained from the compound of Auxiliary Example 84 and 2-(3,4-dimethoxyphenyl)ethanamine.

РХ/МС 453 (М.Н).

Example 58

Preparation of M-(2-(diethylamino)ethyl|-3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-M-(2,2,2-trifluoroethyl)-4,5-dihydrothieno| 3,2-s|quinoline-2-carboxamide hydrochloride

OIE

IF) and

ME

8-40 what Me R

M' Nei ri

By a procedure similar to that of Example 45, the title compound (12 mg, 7 Uo) was obtained as a white powder from the compound of Auxiliary Example 7 (116 mg, 0.29 mmol) and M,

M-diethyl-M'-(2,2,2-trifluoroethyl)ethylenediamine (70 mg, 0.35 mmol). "H-NMR (300 MHz, COSiz) 6: 0.80-1.10 (6H, w), 2.30-2.70 (6H, suh, 3.75 (2H, t, U-5.6 Hz), 4.02 (ZH, s), 4.44 (2H, w d, U-7.8 Gu), 5.86 (2H, s), 7.04 (1H, d, U-8, 4 Gu), 7.26 (1H, t, 9U-7.8 Hz), 7.47 (1H, td, U-8.7, 1.5

Hz), 7.56 (2H, t, 9-7.5 Hz), 7.65-7.70 (1H, m), 7.83 (1H, dd, 9U-7.8, 1.5 Hz ), 8.11 (2H, d, 9U-7.2 Gu).

Example 59

Preparation of 3-methoxy-5-methyl-IM-I(3-(1-methylethoxy)propyl|-4-oxo-4,5-dihydrothieno|3,2-c)quinoline-2-carboxamide

Me

H-Me (c) about ed

M

From the west OMe

M (in)

Me

By a method similar to that given in Example 1, the title compound was obtained from the compound of Auxiliary Example 84 and 3-(1-methylethoxy)propan-1-amine.

РХ/МС 389 (М--Н).

Example 60

Preparation of 3-methoxy-5-methyl-4-oxo-M-I|33-(2-oxopyrrolidin-1-yl)propyl|-4,5-dihydrothienoic|3,2-syquinoline-2-carboxamide

M

(in); ed

M (6)

N j xx OMe

M (6)

Me

By a method similar to that given in Example 1, the title compound was obtained from the compound of Auxiliary Example 84 and 1-(3-aminopropyl)pyrrolidin-2-one.

РХ/МС 414 (М.Н).

Example 61

Preparation of M-(2-aminoethyl)-3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno|3,2-c|quinoline-2-carboxamide hydrochloride

MN. (F) -i- i g s Oome

Mo her ri

A solution of the compound of Example 64 (90 mg, 0.17 mmol) and a 4M ethyl acetate hydrochloride solution (10 mL) in ethyl acetate (20 mL) was stirred at room temperature for 5 hours. The resulting residue was collected by filtration, washed with ethyl acetate and diethyl ether, and dried under reduced pressure to give the title compound (78 mg, 97,905) as a white powder. "H-NMR (300 MHz, DMSO-α) 6: 3.02 (2H, t, U-6.0 Hu), 3.62 (2H, k, U-6.0 Hz), 4.06 ( ЗН, с), 6.00 (2Н, с), 7.36 (1Н, т, 9У-7.4 Hz), 7.50 (1Н, d, У-8.4 Гу), 7.57- 7.59 (ZH, m), 7.65 (1H, t, 9U-7.5 Hz), 7.94 (ZH, w s), 8.06 (IN, dd, U-8.1, 1 .5 Hz), 8.16-8.23 (ZN, m).

Example 62

Preparation of M-(3-aminopropyl)-3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoic3,2-syquinoline-2-carboxamide hydrochloride

MN. at

Am -x OomMe

Mo her r:

By a procedure similar to that of Example 61, the title compound (121 mg, 100 95) was obtained as a white powder from the compound of Example 65 (130 mg, 0.24 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.80-1.90 (2H, m), 2.85 (2H, t, 9U-7.4 Hz), 3.33-3.49 (2Н, m), 4.04 (ЗН, с), 6.00 (2Н, с), 7.36 (1ТН, т, 9У-7.4 Гу), 7.50 (1Н, d, У- 8.1 Gu), 7.56-7.67 (ZN, m), 7.75-7.80 (4H, m), 8.05 (IN, dd, U-7.8, 1.2 Hz ), 8.16-8.23 (ZN, m).

Example 63

Preparation of M-(3-amino-2,2-dimethylpropyl)-3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoyl-3,2-siquinoline-2-carboxamide hydrochloride

MN. about A-K

Me

M Me x s OoMe

Mo NS rya

By a procedure similar to that of Example 61, the title compound (123 mg, 92 95) was obtained as a white powder from the compound of Example 66 (150 mg, 0.26 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.01 (6H, s), 2.69 (2H, k, U9-6.0 Hz), 3.32 (2H, d, U-6 .6 Hz), 4.08 (ZH, s), 6.01 (2H, s), 7.34 (1H, t, 9U-7.8 Hz), 7.51 (1H, d, 9U-8 ,1 Hz), 7.57-7.67 (ZH, m), 7.78 (1H, t, U-7.2 Gu), 7.90 (ZH, w s), 8.06 (1H, dd, 9U-8.1, 1.5 Hz), 8.17-8.19 (ZN, m).

Example 64

Preparation of tert-butyl (2-(|(3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno|3,2-c)quinoline-2-ylcarbonylamino)dethylcarbamate

Me

M-« Me o 0j- o

With X and with ome and

to them (8)

WITH

By a procedure similar to that of Example 25, the title compound (136 mg, 50 95) was obtained as white crystals from the compound of Auxiliary Example 7 (200 mg, 0.51 mmol) and tert-butyl M-(2- aminoethyl)carbamate (122 mg, 0.76 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.37 (9Н, s), 3.10-3.20 (2Н, m), 3.37-3.41 (2Н, m), 4 ... , U-8.4 Hz), 7.55-7.67 (ZH, m), 7.77 (1H, t, 9U-7.5

Hz), 8.04-8.07 (2H, m), 8.16-8.19 (2H, m).

Example 65

Preparation of tert-butyl 3-(|3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno|3,2-c)quinoline-2-ylcarbonylamino)upropyl|carbamate ( ) u-o

M M

M me me oh Me Me

She is still with OoMe

I. ICF) ri

By a procedure similar to that of Example 25, the title compound (136 mg, 50 95) was obtained as white crystals from the compound of Auxiliary Example 7 (200 mg, 0.51 mmol) and tert-butyl M-(Z- aminopropyl)ucarbamate (133 mg, 0.76 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.32 (9Н, s), 1.60-1.70 (2Н, m), 2.90-3.00 (2Н, m), 3 ... 7.5 Hu), 7.49 (1H, d, U-8.4 Hu), 7.55-7.67 (ZH, m), 7.77 (IN, t, U-7.2 Hz) , 8.05 (1H, dd, 9U-7.8, 1.2 Hz), 8.17-8.19 (ZH, m).

Example 66

Preparation of tert-butyl 3-(|3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno|3,2-c)quinoline-2-ylcarbonyl)lamino)-2 ,2-dimethylpropylcarbamate

-o o KV me

M Me

Me

N

WITH

Ministry of Defense

By a procedure similar to that of Example 25, the title compound (205 mg, 69 95) was obtained as white crystals from the compound of Auxiliary Example 7 (200 mg, 0.51 mmol) and 1-Bos-amino-2, 2-dimethyl-1,3-propanediamine (154 mg, 0.76 mmol). "H-NMR (300 MHz, DMSO-av) 5: 1.42 (9H, s), 2.81 (2H, d, 9U-6.3 Hz), 3.13 (2H, d, 9U-6 ,3 Hz), 4.09 (ZH, s), 6.00 (2H, s), 7.11 (IN, w t), 7.35 (1TN, t, 9U-7.5 Hz), 7 .50 (1H, d, U-8.4 Hz), 7.56-7.67 (ZH, m), 7.77 (1H, t, 9U-7.5 Hz), 8.05 (1H, dd, U-8.1, 1.5 Hz), 8.16-8.19 (2H, m), 8.37 (1H, w t).

Example 67

Preparation of M-(2-(dimethylamino)ethyl|-3-methoxy-M-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoyl-3,2-siquinoline-2-carboxamide hydrochloride

Mme. Oh

M

Me

With St. OoMe what her re

To a solution of the compound of Auxiliary Example 7 (200 mg, 0.51 mmol), M, M, M'-trimethylethylenediamine (78 mg, 0.76 mmol) and NOVI (103 mg, 0.76 mmol) in DMF (5 ml) UUZSO (145 mg, 0.76 mmol) was added while cooling on ice, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate. The extracts were combined, washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluate; ethyl acetate/hexane-:2/1) to give M-(2-(dimethylamino)ethyl|-3-methoxy-M-methyl-4-oxo-5-(2-oxo -2-phenylethyl)-4,5-dihydrothieno|3,2-s|quinoline-2-carboxamide (180 mg) in the form of a colorless amorphous substance.

To a solution of M-(2-(dimethylamino)ethyl|-3-methoxy-M-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoi3,2-cquinoline-2-carboxamide (180 mg, 0.38 mmol) in ethyl acetate (10 mL) was added to a 4M solution of hydrochloride in ethyl acetate (0.1 mL), and the resulting precipitate was collected by filtration, washed with diethyl ether, and dried under reduced pressure to afford the title compound (144 mg, 55 95) in the form of a white powder. "H-NMR (300 MHz, DMSO-α) 6: 1.15 (6H, t, 9U-7.1 Hz), 3.10 (ZH, s) , 3.39-3.50 (AN, m), 3.87 (ZH, s), 5.98 (2H, s), 7.33 (1H, t, U-7.5 Gu), 7, 48 (1IN, d, U-7.8 Hu), 7.56 (1H, td, 9U-8.7, 1.2 Hu), 7.64 (2H, t, 9-7.5

Hz), 7.75 (IN, d, 9U-7.5 Hz), 7.96 (1H, dd, 9U-7.8, 1.2 Hz), 8.18 (2H, d, 9U-7 .5 Gu).

Example 68

Preparation of //3-ethoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-M-(2-pyrrolidin-1-ylethyl)-4,5-dihydro-1H-pyrrolyl3,2 -c|quinoline-2-carboxamide c (8) ime. zm

M and A

GG oh eye o

FI

-

By a procedure similar to that of Example 25, the title compound (44.0 mg, 18 95) was obtained as a white powder from the compound of Auxiliary Example 30 (200 mg, 0.495 mmol) and 1-(2-aminoethyl)pyrrolidine (82.1 μl, 0.644 mmol). "H-NMR (300 MHz, DMSO-av) 6: 1.32 (ZH, t, 9U-7.0 Gu), 1.65-1.75 (4H, w), 2.40-2.55 (AN, w), 2.62 (2H, t, 9-6.0 Hz), 3.05-3.47 (2H, m), 4.29 (2H, k, 9U-7.0 Hz) , 4.39 (ZH, s), 5.96 (2H, s), 7.29-7.39 (2H, m), 7.48 (IN, t, 97.8 Hz), 7.63 ( 2H, t, 9U-7.7 Hz), 7.76 (1H, t, 9U-7.4 Hz), 8.12-8.19 (ЗН, m), 8.38 (1H, d, U -8.4 Gu).

Example 69

Preparation of M-(2-(4-hydroxypiperidin-1-yl)ethyl|-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H- pyrrolo|3,2-s|quinoline-2-carboxamide one (U

M

(c) i-

M

Me N

M o OMe

M (8) r:

By a procedure similar to that of Example 25, the title compound (210 mg, 79 95) was obtained as a white powder from the compound of Auxiliary Example 28 (200 mg, 0.512 mmol) and 4-(2-aminoethyl)cyclohexanol (96 .0 mg, 0.606 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.35-1.50 (2H, w), 1.70-1.80 (2H, w), 2.00-2.15 (2H, w), 2.45-2.55 (2Н, шу, 2.70-2.85 (2Н, w), 3.35-3.50 (ЗН, m), 4.01 (ЗН, с), 4.38 (ZH, s), 4.56 (1H, d, 9U-4.5 Hz), 5.97 (2H, s), 7.29-7.40 (2H, m), 7.48 (1H, t, U-7.8 Hz), 7.64 (2H, t, 9U-7.7 Hz), 7.76 (1TN, t, U9-7.2 Gu), 8.12-8 .19 (ZH, m), 8.38 (1H, d, 9U-8.4 Hz).

Example 70

Preparation of 3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-M-(2-piperidin-1-ylethyl)-4,5-dihydro-1H-pyrrolyl3,2-s |quinoline-2-carboxamide o,

M o - M

Me, N g se OomMme sho o

IV) I "h

By a procedure similar to that of Example 25, the title compound (230 mg, 90 95) was obtained as a white powder from the compound of Auxiliary Example 28 (200 mg, 0.512 mmol) and 1-(2-aminoethyl)piperidine (94 .9 μl, 0.666 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.30-1.65 (6H, w), 2.30-2.60 (6H, w), 3.40-3.45 (2H, m), 4.01 (ZN, s), 4.38 (ZN, s), 5.97 (2H, s), 7.29-7.39 (2H, m), 7.45-7.51 (1Н, m), 7.63 (2Н, t, 9-7.5 Hz), 7.73-7.78 (1Н, m), 8.11-8.19 (ЗН, m), 8, 38 (1H, dd, 9U-8,4,1,2 Hz).

Example 71

Preparation of 3-methoxy-1-methyl-N-(2-morpholin-4-ylethyl)-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolyl3,2-s |quinoline-2-carboxamide /79

Ky

M

9 00-

M

Me N

M o OMe

M (8); p;

By a procedure similar to that of Example 25, the title compound (210 mg, 82 95) was obtained as a white powder from the compound of Auxiliary Example 28 (200 mg, 0.512 mmol) and 1-(2-aminoethyl)morpholine (87 .4 μl, 0.666 mmol). "H-NMR (300 MHz, DMSO- av) 6: 2.40-2.55 (6H, w), 3.40-3.50 (2H, w), 3.61 (4H, t, U- 4.2 Hz), 4.01 (ZH, s), 4.37 (ZH, s), 5.97 (2H, s), 7.29-7.40 (2H, m), 7.48 ( 1H, t, 9-7.7 Gu), 7.64 (2H, t, 9-74 Hz), 7.76 (1H, t, 97.4 Hz), 8.12-8.19 (ЗН, m), 8.38 (1H, d, 9U-8.4 Hz).

Example 72

Preparation of M-III-"(dimethylamino)propyl|-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrroloyl3,2-s| quinoline-2-carboxamide me

M

IV) ed. Me

M

Me, N

STILL with OMe

M (c)

WITH

By a procedure similar to that of Example 25, the title compound (163 mg, 67 95) was obtained as a white powder from the compound of Auxiliary Example 28 (200 mg, 0.512 mmol) and M,M-dimethylpropane-1,3- diamine (80.0 μL, 0.666 mmol). "H-NMR (300 MHz, DMSO-av) 5: 1.75-1.84 (2H, m), 2.43 (6H, s), 2.65 (2H, t, 9-7.2 Hz ), 3.34-3.41 (2Н, m), 4.00 (ЗН, с), 4.32 (ЗН, с), 5.97 (2Н, с), 7.29-7.40 ( 2H, m), 7.45-7.51 (1H, m), 7.63 (2H, t, U-7.7 Hz), 7.74-7.78 (IN, m), 8.11 -8.19 (ZH, m), 8.37 (1H, dd, U-8.4, 1.2 Hz).

Example 73

Preparation of 2-C2-(aminomethyl)piperidin-1-ylcarbonyl/-3-methoxy-5-(2-oxo-2-phenylethyl)thieno-3,2-syquinolin-4(5H)-one hydrochloride

MN. (F)

M and s OMe no

MOTO Nei ri

To a solution of the compound of Auxiliary Example 7 (150 mg, 0.38 mmol), 2-(Bos-aminomethyl)piperidine (122 mg, 0.58 mmol) and NOVI (77 mg, 0.58 mmol) in DMF (5 ml) MUZSO (109 mg, 0.58 mmol) was added while cooling on ice and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate. The extracts were combined, washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluate; ethyl acetate/hexane - from 1/1 to 2/1), obtaining tert-butyl ((1-3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl )-4,5-dihydrothienoi|3,2-c|quinoline-2-ylcarbonylpiperidin-2-yl)umethyl|Icarbamate (150 mg) in the form of a colorless oil.

A solution of the obtained tert-butyl |(1-(3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoi3,2-syquinolin-2-ylcarbonyl)ipiperidin-2-yl) methyl carbamate (150 mg) and a 4M ethyl acetate solution of hydrochloride (8 ml) in ethyl acetate (15 ml) were stirred at room temperature for 18 hours.

The resulting precipitate was collected by filtration, washed with diethyl ether and dried under reduced pressure to give the title compound (133 mg, 67 95) as a white powder. "H-NMR (300 MHz, DMSO-α) 6: 1.40-1.90 (6Н, m), 3.00-3.15 (2Н, m), 3.20-3.30 (1Н, m), 3.60-3.80 (1H, m), 3.90 (ZH, s), 4.75-4.90 (IN, w), 5.99 (2H, s), 7.35 (1H, t, 9-74 Hz), 7.48-7.67 (4H, m), 7.77 (1H, t, 9U-7 4

Hz), 7.85-8.00 (4H, m), 8.16-8.19 (2H, m).

Example 74

Preparation of 3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-M-(piperidin-2-ylmethyl)-4,5-dihydrothieno|3,2-

sequinoline-2-carboxamide hydrochloride

N

Ma,

M

8-4 and west OMe cho ne y

By a procedure similar to that of Example 73, the title compound (95 mg, 53 95) was obtained as a white powder from the compound of Auxiliary Example 7 (150 mg, 0.38 mmol) and 2-aminomethyl-M-Bos- piperidine (122 mg, 0.57 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.44-1.91 (6H, m), 2.85 (1H, k, U-12.0 Gu), 3.26 (2H, d , 9U-12.0 Hu), 3.47-3.55 (1Н, m), 3.62-3.69 (1Н, m), 4.06 (ЗН, с), 6.01 (2Н, s), 7.36 (1H, t, 957.5 Hz), 7.51 (IN, d, Uu-68.1

Hz), 7.57-7.67 (ZH, m), 7.78 (1H, t, U-7.4 Hu), 8.07 (1H, dd, 9U-7.8, 1.2 Hu ), 8.18 (2H, d, U-8.4 Hz), 8.27 (1H, t, 9-6.2 Hz), 8.50-8.70 (1H, m), 8.70-8 .85 (1H, m).

Example 75

Preparation of 3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-M-(pyrrolidin-2-ylmethyl)-4,5-dihydrothieno|3,2-syquinoline-2-carboxamide hydrochloride

N

M o -

N

EE loh OmMe about her re

By a procedure similar to that of Example 73, the title compound (126 mg, 65 95) was obtained as a white powder from the compound of Auxiliary Example 7 (150 mg, 0.38 mmol) and 2-aminomethyl-M-Bos- pyrrolidine (122 mg, 0.57 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.63-1.75 (1H, m), 1.83-2.10 (ZH, m), 3.11-3.27 (2H, m), 3.61-3.76 (ZH, m), 4.08 (ZH, s), 6.01 (2H, s), 7.36 (1H, t, 9U-7.5 Hz), 7.51 (1H, d, U-8.4 Hz), 7.57-7.67 (ZH, m), 7.78 (1H, t, 9U-7.5 Hz), 8.07 (1H , dd, U9-7.8, 1.2 Hz), 8.16-8.19 (2H, m), 8.40 (1H, t, U-5.9 Hz), 8.80-9, 20 (2H, w).

Example 76

Preparation of 3-methoxy-IM-I3-(3-methyl-1H-pyrazol-1-yl)propyl|-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoi3,2- sequinoline-2-carboxamide o

Shaklya and about them MO tme in OMe

M (o; ra

By a method similar to that given in Example 25, the title compound (113 mg, 58 95) was obtained as a white powder from the compound of Auxiliary Example 7 (150 mg, 0.38 mmol) and (3-methylpyrazol-1-yl )upranamine ("79 mg, 0.57 mmol). "H-NMR (300 MHz, DMSO-av) 6: 2.02 (2H, t, 9U-6.9 Hz), 2.15 (ZH, s), 3.26-3.35 (2H, m ), 4.04 (ZH, s), 4.09 (2H, t, U-6.9 Gu), 5.99 (2H, s), 7.35 (1TN, t, 9-7.5 Hz ), 7.49 (1H, d, 9U-8.4 Hz), 7.55-7.67 (AN, m), 7.77 (IN, t, U-7.5 Hz), 8.05 (1H, dd, 9-81, 1.2 Gu), 8.03-8.19 (4H, m).

Example 77

Preparation of 3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-M-piperidin-4-yl-4,5-dihydro-1H-pyrrolo|3,2-siquinoline- 2-carboxamide

NN

/x b me, ate

More than OME

M (o) x

According to a method similar to the method given in Example 25, tert-butyl 4-(|3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1 H -pyrrolo|3,2-c)quinoline-2-ylcarbonyl)amino)piperidine-1-carboxylate (615 mg) was obtained as a white powder from the compound of Auxiliary Example 28 (404 mg, 1.00 mmol) and 4-amino- 1-Boc-piperidine (260 mg, 1.33 mmol).

Thus obtained tert-butyl 4-(|3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrroloyl3,2-si|quinoline- 2-ylcarbonylamino)piperidine-1-carboxylate (610 mg) and trifluoroacetic acid (5 mL) were stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, saturated sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on amino silica gel (eluate; ethyl acetate/methanol-20/1) and the resulting solid was recrystallized from ethyl acetate-ethanol to give the title compound (430 mg, 85 95) as white crystals. "H-NMR (300 MHz, DMSO-α) 6: 1.34-1.46 (2H, m), 1.78-1.84 (2H, m), 1.90-2.20 (1H, w)y, 2.50-2.60 (2H, m), 2.85-3.00 (2H, w), 3.80-3.95 (1H, m), 3.98 (ZH, s ), 4.32 (ZH, s), 5.97 (2H, s), 7.29-7.39 (2H, m), 7.45-7.50 (IN, m), 7.63 ( 2H, t, 9U-7.5 Gu), 7.76 (1H, t, U-7.5 Hz), 7.86 (1H, d, 9U-7.8 Hz), 8.16-8, 18 (2H, m), 8.37 (1H, dd, U-8,4,1,2 Hz).

Example 78

Preparation of 3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-M-pyridin-3-yl-4,5-dihydro-1H-pyrrolo|3,2-siquinoline- 2-carboxamide

M

oh oh -

M

Me, N

Zh p OoMe

M o z

A mixture of the compound of Auxiliary Example 28 (200 mg, 0.512 mmol), 3-aminopyridine (60.6 mg, 0.644 mmol), NATI (245 mg, 0.644 mmol), M, M'-disopropylethylamine (336 μl, 1.93 mmol) and DMF (5 ml) were stirred at room temperature for 15 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The extracts were combined, washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by amino silica gel chromatography (eluate; ethyl acetate) and the resulting solid was recrystallized from THF to give the title compound (83.0 mg, 36 95) as white crystals. "H-NMR (300 MHz, DMSO-α) 6:4.07 (ZH, s), 4.33 (ZH, s), 6.00 (2H, s), 7.32-7.44 (ZH, m ), 7.49-7.54 (1H, m), 7.64 (2H, t, 9U-7.5 Hz), 7.77 (1H, t, 9-7.5 Hz), 8.17 -8.22 (ZH, m), 8.33 (1H, dd, U-8.3, 1.1 Hz), 8.41 (1H, dd, U-8,3,1.1 Gu), 8.91 (1H, d, 9-21 Gu), 10.31 (1H, s).

Example 79

Preparation of M-|1-(2-hydroxyethyl)piperidin-4-yl|-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H- pyrrolo|3,2-s|quinoline-2-carboxamide series in me. M

MORE t OMe

M (c) re 1) A mixture of the compound of Example 77 (200 mg, 0.399 mmol), 2-bromoethanol (42.5 μl, 0.599 mmol), potassium carbonate (248 mg, 1.80 mmol) and DMF (5 ml) was stirred at 100 "C for 15 hours.

The reaction mixture was diluted with water and extracted with ethyl acetate. The extracts were combined, washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure.

The residue was purified by amino silica gel chromatography (eluate; ethyl acetate) and the resulting solid was recrystallized from ethyl acetate-ethanol to give the title compound (68.0 mg, 33 95) as white crystals. "H-NMR (300 MHz, DMSO-α) 6: 1.51-1.62 (2H, m), 1.75-1.90 (2H, w), 2.18 (2H, t, 9U- 10. 5 Hz), 2.40 (2H, t, 95.9 Hz), 2.70-2.85 (2H, w), 3.47-3.52 (2H, m), 3.75- 3.90 (1H, w), 3.98 (ZH, s), 4.32-4.38 (AN, m), 5.97 (2H, s), 7.29-7.39 (2H, m), 7.47 (1TN, t, 9U-7.6 Hz), 7.63 (2Н, t, 9У-7.6 Hz), 7.76 (1Н, t, У-7.1 Hz) , 7.87 (1H, d, 9U-7.5 Hz), 8.17 (2H, d, 9-7.6 Hz), 8.37 (1H, d, 9U-8.4 Hz).

2) The white powder was recrystallized from ethanol-water to give the title compound as white crystals. Melting point 20220

Example 80

Preparation of 3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-M-(pyridin-2-ylmethyl)-4,5-dihydro-1H-pyrrolo|3,2- c) quinoline-2-carboxamide hydrochloride

M--

ate me

M s OMe

M o o

NSI

By a method similar to the method given in Example 25, 3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-M-(pyridin-2-ylmethyl)-4,5-dihydro -1H-pyrrole|3,2-c|quinoline-2-carboxamide was obtained as a white powder from the compound of Auxiliary Example 28 (200 mg, 0.512 mmol) and 2-(aminomethyl)pyridine (69.6 mg, 0.644 mmol).

The title compound (222 mg, 87 95) was obtained as a white powder from the thus obtained 3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-M-(pyridine-2 -ylmethyl)-4,5-dihydro-1H-pyrrolo|3,2-c)quinoline-2-carboxamide using a method similar to that described in Example 30. "H-NMR (300 MHz, DMSO-α) 6 :4.08 (ZH, s), 4.34 (ZH, s), 4.85 (2H, d, 9U-5.7 Hz), 5.98 (2H, s), 7.30-7.42 ( 2H, m), 7.47-7.52 (1H, m), 7.64 (2H, t, 9U-7.5 Hz), 7.74-7.85 (ЗН, m), 8.16 -8.19 (2H, m), 8.31-8.40 (2H, m), 8.77-8.84 (2H, m).

Example 81

Preparation of 3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-M-(piperidin-2-ylmethyl)-4,5-dihydro-1H-pyrroloyl-3,2-siIquinoline-2 -carboxamide hydrochloride

N

M ak B,

M

Me N

M p OMe

M (6) (6)

NS

By a procedure similar to that of Example 73, the title compound (230 mg, 89 95) was obtained as a white powder from the compound of Auxiliary Example 28 (200 mg, 0.512 mmol) and 2-(aminomethyl)-1-M- Vos-piperidine (138 mg, 0.644 mmol). "H-NMR (300 MHz, DMSO-av) 6: 1.40-1.95 (6H, w), 2.70-2.95 (1IN, w), 3.15-3.35 (2H, w), 3.46-3.69 (2Н, m), 4.03 (ЗН, с), 4.36 (ЗН, с), 5.98 (2Н, с), 7.30-7.41 (2H, m), 7.47-7.52 (1H, m), 7.64 (2H, t, 9-7.7 Gu), 7.76 (IN, t, U-7.5 Hz) . .90 (1H, t).

Example 82

Preparation of 3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-M-(2-pyrrolidin-1-ylethyl)-4,5-dihydrothieno-3,2-syquinoline-2-ylcarboxamide hydrochloride

MN about

M

8-4 BUT not with oMe

M (c)

WITH

By a procedure similar to that of Example 73, the title compound (114 mg, 47 95) was obtained as a white powder from the compound of Auxiliary Example 7 (150 mg, 0.38 mmol) and 2-aminoethyl-M-Boc- pyrrolidine (122 mg, 0.57 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.50-1.65 (1Н, m), 1.80-2.10 (5Н, m), 2.14-2.25 (1Н, m), 3.10-3.20 (2Н, m), 3.35-3.60 (2Н, m), 4.05 (ЗН, с), 6.00 (2Н, с), 7.35 (1TN, t, 9U-7.5 Hz), 7.50 (1TN, d, 9U-8.7 Hz), 7.56-7.67 (ЗН, m), 7.77 (1Н, t, U-7.5 Hz), 8.05 (1Н, dd, U-7.8, 1.2 Gu), 8.16-8.20 (ЗН, m), 8.50-9.50 (2Н , w).

Example 83

Preparation of 33-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-M-(2-piperidin-1-ylethyl)-4,5-dihydrothieno|3,2-syquinoline-2-carboxamide hydrochloride

V, (o, t i

I still have her

H

By a method similar to that given in Example 67, the title compound (147 mg, 53 95) was obtained as a white powder from the compound of Auxiliary Example 7 (200 mg, 0.51 mmol) and 1-(2-aminoethyl)piperidine (98 mg, 0.76 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.30-1.50 (1Н, m), 1.65-1.80 (5Н, m), 2.85-3.00 (2Н, m), 3.26 (2H, w, 9-5.1 Gu), 3.53 (2H, w d, 9U-11.1 Gu), 3.73 (2H, k, 9U-5.7 Hz ), 4.06 (ZH, s), 6.00 (2H, s), 7.36 (1TN, t, 9-7.5

Hz), 7.50 (1H, d, U-8.4 Hz), 7.57-7.67 (ZH, m), 7.77 (1H, t, 9U-7.5 Hz), 8, 06 (1H, dd, 9U-8.1, 1.5 Hz), 8.16 (IN, d, 9U-1.5 Gu), 8.19 (1H, s), 8.40 (1H, t , U-5.7 Hz), 9.80-9.90 (1H, w).

Example 84

Preparation of 3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-M-piperidin-3-yl-4,5-dihydro-1H-pyrrolo|3,2-c) quinoline-2-carboxamide hydrochloride

M what; b000- their me. /N m ra Zhe -ZOoMe fi pe -ya mmoo o r Ne s de

By a procedure similar to that of Example 73, the title compound (67.1 mg, 27 95) was obtained as a white powder from the compound of Auxiliary Example 28 (200 mg, 0.512 mmol) and 3-amino-1-M- Vos-piperidine (129 mg, 0.644 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.55-2.05 (4H, m), 2.75-3.00 (2H, m), 3.20 (1H, d, 9U- 13.2 Gu), 3.25-3.40 (IN, w), 3.99 (ЗН, с), 4.20-4.30 (1Н, w), 4.31 (ЗН, с), 5.98 (2H, s), 7.30-7.41 (2H, m), 7.46-7.52 (1H, m), 7.64 (2H, t, 9-7.7 Hz) , 7.73-7.79 (1H, m), 8.05 (1H, d, U-8.1 Gu), 8.16-8.19 (2H, m), 8.38 (1H, dd , 9U-8.3, 1.4 Hz), 8.85-9.05 (2H, w).

Example 85

Preparation of M-Itrano-2-aminocyclohexyl|-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5- dihydro-1H-pyrrole|3,2-c) quinoline-2-carboxamide

Mr. U

Oh, -N-

Kt -

Me M MA. "M N shch ich trane

Fi OM o she r: sh

According to a method similar to the method given in Example 73, M-Igrans-2-aminocyclohexyl|-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro- 1H-pyrrole|3,2-c|quinoline-2-carboxamide hydrochloride was prepared from the compound of Auxiliary Example 28 (200 mg, 0.512 mmol) and M-Boc-trans-1,2-diaminocyclohexane (138 mg, 0.644 mmol).

To the thus obtained M-Itrans-2-aminocyclohexyl|-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo|3,2 -c|quinoline-2-carboxamide hydrochloride was added to a saturated solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by amino silica gel chromatography (eluate; ethyl acetate/methanol-20/1) and the resulting solid was recrystallized from ethyl acetate-ethanol to give the title compound (80.0 mg, 33,905) as white crystals. "H-NMR (300 MHz, DMSO-av) 6: 1.10-1.40 (AN, w), 1.50-1.75 (4H, sh, 1.70-1.90 (1H, w ), 1.90-2.05 (1H, w), 2.45-2.60 (1H, w), 3.45-3.60 (1H, w), 3.97 (ZH, s), 4.30 (ZH, s), 5.97 (2H, s), 7.29-7.39 (2H, m), 7.47 (IN, t, 7.7 Hz), 7.63 (2H , t, 9U-7.7 Hz), 7.76 (1TN, t, U-7.4 Gu), 7.90 (1Н, d, U-7.8 Hz), 8.17 (2Н, d , 9U-7.7 Hz),

8.37 (IN, d, 9-81 Hz).

Example 86

Preparation of 3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-M-pyrrolidin-3-yl-4,5-dihydro-1H-pyrrolo|3,2-s| quinoline-2-carboxamide hydrochloride

N

M sq

M

Me, N

OMG

M (8)

E | Her

By a procedure similar to that of Example 73, the title compound (122 mg, 50 95) was obtained as a white powder from the compound of Auxiliary Example 28 (200 mg, 0.512 mmol) and 3-amino-1-M-Voc- pyrrolidine (120 mg, 0.644 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.94-2.05 (1H, m), 2.20-2.32 (1H, m), 3.17-3.49 (4H, m), 4.00 (ZN, s), 4.30 (ZN, s), 4.58-4.69 (1H, m), 5.98 (2H, s), 7.30-7.40 (2H, m), 7.46-7.52 (1H, m), 7.64 (2H, t, 9U-7.5 Gu), 7.73-7.79 (1H, m), 8, 16-8.19 (2H, m), 8.26 (IN, d, 9U-6.9 Hz), 8.38 (1H, dd, 9U-8.3, 1.1 Gu), 9.10 -9.30 (2H, w).

Example 87

Preparation of M-(3-(dimethylamino)-2,2-dimethylpropyl|-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1 H- pyrrolo|3,2-cIquinoline-2-carboxamide hydrochloride

Me

YAM, / M o, utteme"?

Me M Me x N her

FI with tOME

I dream of her sh sh sh

According to a method similar to the method given in Example 25, M-3-(dimethylamino)-2,2-dimethylpropyl|-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)- 4,5-dihydro-1H-pyrrolo|3,2-c|quinoline-2-carboxamide was obtained as a white powder from the compound of Auxiliary Example 28 (200 mg, 0.512 mmol).

The title compound (203 mg, 76 95) was obtained in the form of a white powder from the thus obtained M-I(3-«(dimethylamino)-2,2-dimethylpropyl|-3-methoxy-1-methyl-4-oxo- 5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo|3,2-quinoline-2-carboxamide using a method similar to that described in Example 30. "H-NMR (300 MHz , DMSO-аv) 6: 1.12 (6Н, с), 2.86 (ЗН, с), 2.87 (ЗН, с), 3.03-3.07 (2Н, с), 3.33 -3.40 (2H, w)y, 4.04 (ZH, s), 4.30 (ZH, s), 5.99 (2H, s), 7.30-7.41 (2H, m) , 7.46-7.52 (1H, m), 7.64 (2H, t, 9-7.5 Gu), 7.716 (IN, t, 9-7.4 Hz), 8.16-8, 21 (ZH, m), 8.38 (1TN, dd, U-8.3, 1.1 Gu), 9.50-9.70 (1H, w).

Example 88

Preparation of /M-(4-aminocyclohexyl)-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-

1H-pyrroloyl3,2-siquinoline-2-carboxamide hydrochloride

MN. at

ate me

M m she OoMe

M (o) ; | Not

By a procedure similar to that of Example 73, the title compound (121 mg, 47 95) was obtained as a white powder from the compound of Auxiliary Example 28 (200 mg, 0.512 mmol) and tert-butyl (4-aminocyclohexyl)carbamate ( 138 mg, 0.644 mmol). "H-NMR (300 MHz, DMSO-av) 6: 1.18-1.34 (1H, w), 1.55-1.75 (IN, w), 1.75-1.90 (2H, sh, 1.95-2.20 (1H, sh)y, 2.60-2.81 (2H, m), 3.15-3.45 (ZH, m), 4.01 (ZH, s) , 4.30 (ZH, s), 5.98 (2H, s), 7.30-7.40 (2H, m), 7.46-7.51 (IN, m), 7.64 (2H , t, 957.5 Hz), 7.74-7.79 (1H, m), 8.16-8.20 (ZH, m), 8.38 (1H, dd, 9U-8.3, 1 .4 Gu), 8.65-8.95 (2H, w).

Example 89

Preparation of 2-C(3B)-3-aminopyrrolidin-1-ylcarbonyl)-3-methoxy-1-methyl-5-(2-oxo-2-phenylethyl)-1,5-dihydro-4H-pyrrolo|3,2 -c|quinolin-4-one hydrochloride (c)

Me. widow

M them "Mn, according to TU OMe

This is what we eat; r on

By a procedure similar to that of Example 73, the title compound (190 mg, 78 95) was obtained as a white powder from the compound of Auxiliary Example 28 (200 mg, 0.512 mmol) and tert-butyl (ZK)-pyrrolidine-3 -ylcarbamate (120 mg, 0.644 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.95-2.15 (1Н, m), 2.15-2.40 (1Н, m), 3.57-3.92 (8Н, m), 4.03-4.10 (ZN, shu, 5.98 (2H, s), 7.28-7.40 (2H, m), 7.44-7.49 (1H, m), 7.63 (2H, t, 9-7.5 Hu), 7.76 (1H, t, 9U-7.4 Hu), 8.16- 8.19 (2H, m), 8.30-8 .50 (4H, w).

Example 90

Preparation of 2-1(35)-3-aminopiperidin-1-ylcarbonyl)-3-methoxy-1-methyl-5-(2-oxo-2-phenylethyl)-1,5-dihydro-4H-pyrrolo|3,2 -c|quinolin-4-one hydrochloride would

Me. M

М - х МН - ОМе 2 (5) m7ta o not

FI yet

By a procedure similar to that of Example 73, the title compound (190 mg, 78 95) was obtained as a white powder from the compound of Auxiliary Example 28 (200 mg, 0.512 mmol) and tert-butyl (35)-piperidine-3 -ylcarbamate (120 mg, 0.644 mmol). "H-NMR (300 MHz, DMSO-av) 5: 1.45-2.00 (ZH, w), 2.00-2.15 (IN, w), 2.75-3.30 (4H, w), 3.65-3.85 (0.5Н, w)y, 3.91 (ЗН, с), 4.03 (ЗН, с), 4.40-4.75 (0.5Н, w ), 5.97 (2H, s), 7.29-7.40 (2H, m), 7.44-7.49 (1H, m), 7.64 (2H, t, 9-7.5 Hz), 7.76 (1H, t, U-7.4 Hz), 8.10-8.20 (5H, w), 8.34 (1H, d, 9-7.8 Hz).

Example 91

Preparation of 2-13-(aminomethyl)piperidin-1-ylcarbonyl)-3-methoxy-1-methyl-5-(2-oxo-2-phenylethyl)-1,5-dihydro-4H-pyrrolo|3,2-s | of quinolin-4-one hydrochloride o Ika,

Me, »-m / at eh M -oMe MN,

C as ZA B 9) ) naTei

Yes, I am

By a procedure similar to that of Example 73, the title compound (170 mg, 66 95) was obtained as a white powder from the compound of Auxiliary Example 28 (200 mg, 0.512 mmol) and tert-butyl (piperidin-3-ylmethyl) carbamate (143 mg, 0.644 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.20-1.60 (2H, w), 1.60-2.00 (ZH, w), 2.55-3.05 (ZH, w), 3.10-3.30 (1Н, w)y, 3.60-3.80 (1ТН, w), 3.90 (ЗН, с), 4.01 (ЗН, с), 4, 25-4.60 (1H, w), 5.98 (2H, s), 7.28-7.39 (2H, m), 7.46 (IN, t, 7.7 Gu), 7.64 (2H, t, 9U-7.7 Hz), 7.76 (1H, t, 9U-7.1 Hz), 7.90-8.25 (5H, w), 8.33 (1H, d, 9-81 Hz).

Example 92

Preparation of /- M-(2-(dimethylamino)-1-methylethyl|-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrole |3,2-s|quinoline-2-carboxamide

Me

Me, M-Me 0000 -M

Me. /- N

M Ya t Ky pa r still I zo o.

With ch

By a procedure similar to that of Example 25, the title compound (67.0 mg, 29 90) was obtained as a white powder from the compound of Auxiliary Example 28 (440 mg, 1.01 mmol) and 1-(dimethylamino)isopropylamine (68.1 mg, 0.666 mmol). "H-NMR (300 MHz, DMSO-av) 6: 1.20 (ZH, d, 9-6.0 Hz), 2.20 (6H, s), 2.20-2.27 (1H, m ), 2.39-2.46 (1Н, m), 3.97 (ЗН, с), 3.98-4.10 (1Н, m), 4.36 (ЗН, с), 5.97 ( 2H, s), 7.29-7.39 (2H, m), 7.45-7.51 (1H, m), 7.63 (2H, t, 7.5 Hz), 7.73-7 .79 (1H, m), 7.96 (1H, d, U-6.6 Hz), 8.16-8.19 (2H, m), 8.38 (1H, dd, 9U-8.1 , 1.2 Hz).

Example 93

Preparation of 2-1|(3B)-3-aminopiperidin-1-ylcarbonyl)-3-methoxy-1-methyl-5-(2-oxo-2-phenylethyl)-1,5-dihydro-4H-pyrrolo|3, 2-c|quinolin-4-one hydrochloride o /

Me. south

MORE ( chu to Me MN. more (V

And she 0-0 No and under

By a procedure similar to that of Example 73, the title compound (190 mg, 75 95) was obtained as a white powder from the compound of Auxiliary Example 28 (200 mg, 0.512 mmol) and tert-butyl (ZK)-piperidine-3 -ylcarbamate (133 mg, 0.666 mmol). "H-NMR (300 MHz, DMSO-av) 5: 1.45-2.00 (ZH, w), 2.00-2.15 (IN, w), 2.75-3.30 (4H, w), 3.65-3.85 (0.5Н, w)y, 3.91 (ЗН, с), 4.03 (ЗН, с), 4.40-4.75 (0.5Н, w ), 5.97 (2H, s), 7.29-7.40 (2H, m), 7.44-7.49 (1H, m), 7.64 (2H, t, 9-7.7 Hz), 7.76 (1H, t, U-7.4 Gu), 8.10-8.30 (5H, w), 8.34 (1H, d, 9-81 Hz).

Example 94

Preparation of 3-methoxy-M-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-M-(2-piperidin-1-ylethyl)-4,5-dihydrothienoyl3,2-siquinoline-2-carboxamide hydrochloride

In, about -ЖБ-

M

Z x Me s OoMe mo her

IN

By a procedure similar to that of Example 67, the title compound (154 mg, 7395) was obtained as a white powder from the compound of Auxiliary Example 7 (150 mg, 0.38 mmol) and 1-(2-M'-methylaminoethyl ) piperidine (108 mg, 0.76 mmol). "H-NMR (300 MHz, SOS") 5: 1.25-1.45 (1H, m), 1.60-1.90 (4H, m), 2.80-3.00 (2H, w ), 3.11 (ZH, s), 3.35-3.40 (2H, m), 3.40-3.65 (2H, w), 3.80-3.90 (5H, m), 5.99 (2H, s), 7.35 (1H, t, 9-7.5 Hz), 7.48-7.67 (AN, m), 7.77 AN, t, U-7.5 Hz), 7.98 (1H, dd, 9U-7.8, 1.2 Hz), 8.16-8.19 (ZH, m), 9.75-9.90 (1H, w).

Example 95

Preparation of 3-methoxy-M-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-M-(2-pyrrolidin-1-ylethyl)-4,5-dihydrothienoyl3,2-siquinoline-2-carboxamide hydrochloride

MV, Fr

M, x Me with OoMe

Mo Nei ria

By a procedure similar to that of Example 67, the title compound (153 mg, 7495) was obtained as a white powder from the compound of Auxiliary Example 7 (150 mg, 0.38 mmol) and 1-(2-M'-methylaminoethyl )pyrrolidine (98 mg, 0.76 mmol). "H-NMR (300 MHz, SOS") 8: 1.75-2.10 (4Н, m), 2.90-3.15 (5Н, m), 3.35-3.50 (2Н, m ), 3.50-3.80 (2H, w), 3.83-3.90 (5H, m), 5.99 (2H, s), 7.35 (1H, t, 9U-7.5 Hz), 7.48-7.67 (AN, m), 7.77 (1H, t, U9-7.5 Hz), 7.97 (1H, dd, U-7.8, 1.2 Hz ), 8.16-8.19 (2H, m), 10.35-10.65 (1H, w).

Example 96

Preparation of 3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-M-(25)-piperidin-2-ylmethyl-4,5-dihydrothienoyl-3,2-siquinoline-2-carboxamide hydrochloride

N

M a, i

P (5) is the same as ТОМе

M'o NOSI r

By a procedure similar to that of Example 73, the title compound (80 mg, 57 95) was obtained as a white powder from the compound of Auxiliary Example 7 (107 mg, 0.27 mmol) and (5)-2-(Voc -aminomethyl)piperidine (58 mg, 0.27 mmol). "H-NMR (300 MHz, SOSI") 6: 1.35-1.90 (6H, m), 3.00-3.40 (AN, m), 3.90 (ZN, s), 4, 70-4.90 (1H, w), 5.99 (2H, s), 7.35 (IN, t, 9-7.5 Hz), 7.48-7.67 (AN, m), 7 .77 (1H, t, U-7.5 Hz), 7.95-8.19 (6H, m).

Example 97

Preparation of 3-methoxy-N-(2-(1-methylethyl)amino|ethyl)-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoyl3,2-syquinoline-2-carboxamide

Me n i- o 00,--- Me m pk; with OoMe

M (F)

To a mixture of a solution of the compound of Example 61 (150 mg, 0.32 mmol) and acetone (0.2 ml) in methanol (5 ml)-

Sodium cyanoborohydride (20 mg, 0.32 mmol) was added to OME (5 mL) and the mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate. The extracts were combined, washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by amino silica gel chromatography (eluate; ethyl acetate) and the resulting white solid was recrystallized from ethyl acetate-hexane to give the title compound (69 mg, 95) as white crystals. "H-NMR (300 MHz, SOSIz) 5: 1.09 (6H, d, 9U-6.3 Hz), 2.83-2.89 (ZH, m), 3.57 (2H, k, 95 .7 Hz), 4.16 (ZH, s), 5.87 (2H, s), 7.02 (1H, d, 9U-8.4 Gu), 7.26-7.28 (1H, m ), 7.44-7.50 (1H, m), 7.56 (2H, t, 9U-7.5 Hz), 7.66 (IN, t, U-7.5 Hz), 7.91 (1Н, dd, 9-81, 1.2 Gu), 8.10-8.13 (ЗН, m).

Example 98

Preparation of 3-methoxy-M-13-(1-methylethyl)amino|propyl)-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoyl3,2-siquinoline-2-carboxamide

Me "-Me

M

(8) Jan

M g i OMe

M (o);

WITH

By a procedure similar to that of Example 97, the title compound (9 mg, 95) was prepared as a white powder from the compound of Example 62 (190 mg, 0.38 mmol). "H-NMR (300 MHz, SOS") 6: 1.08 (6H, d, U-6.3 Hz), 1.75-1.88 (2H, m), 2.73 (2H, t, U-6.9 Gu), 2.76-2.85 (IN, m), 3.58 (2Н, k, 9У-6.4 Hz), 4.14 (ЗН, с), 5.87 ( 2H, s), 7.02 (1H, d, 9U-8.7 Hz), 7.20-7.28 (1H, m), 7.44-7.50 (1H, m), 7.56 (2H, t, U-7.5 Hz), 7.65-7.68 (1H, m), 7.80 (1H, w t), 7.91 (1H, dd, U-7.8, 1.2 Gu), 8.10-8.13 (2H, m).

Example 99

Preparation of 3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-M-(piperidin-3-ylmethyl)-4,5-dihydro-1H-pyrroloyl-3,2-siIquinoline-2 -carboxamide hydrochloride n

A-y' 4 o U h y

Me x " Kk, x Nn

M -65O r still I OME ve na

SHI

SHI

By a method similar to that given in Example 73, the title compound (190 mg, 75 95) was obtained as a white powder from the compound of Auxiliary Example 28 (200 mg, 0.512 mmol) and tert-butyl 3-(aminomethyl)piperidine- 1-carboxylate (143 mg, 0.666 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.15-1.35 (1H, w), 1.50-1.90 (ZH, w), 1.95-2.15 (1H, w), 2.64 (1H, t, 3-6.2 Hz), 2.78 (IN, t, U-5.7 Hz), 3.15-3.45 (AN, shu, 4.01 (ZN, s), 4.30 (ZN, s), 5.98 (2H, s), 7.29-7.A41 (2H, m), 7.48 (IN, t, U-7.6 Hz), 7.64 (2Н, т, 9-7.6 Hz), 7.76 (1ТН, т, У-7.4 Gu), 8.16-8.19 (ЗН, m), 8, 37 (1H, d, 3-81 Gu), 8.55-8.85 (2H, w).

Example 100

Preparation of /- M-(1-aminocyclohexyl)methyl|-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolyl3,2-s |quinoline-2-carboxamide hydrochloride

Nzh, U o a h

Me z-m -i h

TP and U. ome

Yes, that's about it

F

SHI

I

By a procedure similar to that of Example 73, the title compound (80.0 mg, 30 95) was obtained as a white powder from the compound of Auxiliary Example 28 (200 mg, 0.512 mmol) and tert-butyl (1-(aminomethyl )cyclohexylcarbamate (147 mg, 0.644 mmol). "H-NMR (300 MHz, DMSO-α) 5: 1.25-1.70 (TON, w), 3.61 (2H, d, U-6.3 Hz), 4.04 (ZH, s), 4.34 (ZH, s), 5.98 (2H, s), 7.31-7.42 (2H, m), 7.50 (1H, t , U-7.6 Hz), 7.64 (2H, t, 9U-7.6 Hz), 7.77 (1H, t, U-7.5 Gu), 7.680- 8.00 (ЗН, w ), 8.16-8.22 (ZN, m), 8.39 (1H, d, 9-84 Gu).

Example 101

Preparation of M-(1-(2-hydroxyethyl)piperidin-2-yl|methyl)-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro- 1H-pyrrolo|3,2-s|quinoline-2-carboxamide o me m M- ch-i Go ( skh Ko oMme ten she i Mch o g

What is it?

By a procedure similar to that of Example 79, the title compound (471 mg, 39 90) was obtained as a white powder from the compound of Example 81 (200 mg, 0.399 mmol) and 2-bromomethanol (24.2 μl, 0.341 mmol ). "H-NMR (300 MHz, DMSO-α) 6: 1.20-1.75 (6H, w), 2.20-3.10 (5H, w), 3.40-3.65 (4H, w), 3.98-4.05 (ZH, w), 4.15-4.50 (AN, w), 5.98 (2H, s), 7.29-7.40 (2H, m) , 7.45-7.51 (1H, m), 7.64 (2H, t, 9-7.7 Gu), 7.76 (1H, t, uU-7.5 Hz), 8.00- 8.20 (ZH, m), 8.39 (1TN, dd, 9U-8.3, 1.1 Hz).

Example 102

Preparation of M-(1-(2-hydroxyethyl)piperidin-3-yl|methyl)-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro- 1H-pyrrolo|3,2-c|quinoline-2-carboxamide and

Ai

Me z-m m dv ve -ov to g

SHI a

By a procedure similar to that of Example 79, the title compound (85.2 mg, 50 90) was obtained as a white powder from the compound of Example 99 (160 mg, 0.306 mmol) and 2-bromomethanol (65.0 μl, 0.918 mmol). "H-NMR (300 MHz, DMSO-dv) 6: 0.90-1.10 (1H, suh, 1.35-1.55 (1H, suh), 1.55-1.90 (4H, suh , 1.96 (1H, t, 9U-7.1 Gu), 2.36 (2H, t, 9U-6.3 Hz), 2.72 (1H, d, 9U-9.9 Hz), 2 .83 (IN, d, 9U-7.5 Hz), 3.15-3.30 (2H, w), 3.45-3.51 (2H, m), 3.99 (ZH, s), 4.30-4.34 (AN, m), 5.97 (2H, s), 7.29-7.39 (2H, m), 7.47 (1H, t, U-7.7 Gu) , 7.63 (2H, t, 9U-7.7 Hz), 7.76 (1H, t, U-7.5 Hu), 8.02 (1H, t, U-6.0 Hu), 8 .17 (2H, d, 9-7.7 Hz), 8.37 (1H, d, 9U-8.1 Hz).

Example 103

Preparation of M-(2-aminoethyl)-3-methoxy-M-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoic|3,2- syquinoline-2-carboxamide hydrochloride

MN, (o) i-

M, x Me s OoMme her

M o

WITH

To a solution of the compound of Auxiliary Example 7 (300 mg, 0.760 mmol), 1-Bos-amino-2-methylaminoethane hydrochloride (321 mg, 1.52 mmol), triethylamine (154 mg, 1.52 mmol) and NOVI (206 mg, 1.52 mmol) in DMF (10 mL) was added MUZSO (290 mg, 1.52 mmol) while cooling on ice and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate. The extracts were combined, washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure.

The residue was purified by chromatography on silica gel (eluate; ethyl acetate/hexane-2/1) to give tert-butyl 32-(13-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5- dihydrothienoic|Z3,2-c|quinolin-2-yl|carbonylmethyl)amino|ethylcarbamate (230 mg) in the form of a colorless oil.

A solution of the obtained tert-butyl 32-(13-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoi3,2-syquinoline-2-ylcarbonylmethyl)amino|ethyl carbamate (230 mg) and A 4M ethyl acetate solution of hydrochloride (8 mL) in ethyl acetate (15 mL) was stirred at room temperature for 2 hours.

The resulting precipitate was collected by filtration, washed with diethyl ether and dried under reduced pressure to give the title compound (178 mg, 48 95) as a white powder. "H-NMR (300 MHz, DMSO-α) 5: 3.00-3.10 (5H, m), 3.60-3.75 (2H, m), 3.89 (ZH, s), 5 .99 (2H, s), 7.35 (IN, t, 9U-7.5 Hz), 7.49 (1TN, d, 9U-8.7 Hz), 7.56 (1H, d, 9U- 7.2 Hz), 7.64 (2H, t, U-7.5 Hz), 7.77 (1H, t, U-7.2

Hz), 7.80-7.98 (AN, m), 8.17 (2H, d, 9-7.5 Gu).

Example 104

Preparation of M-(3-aminopropyl)-3-methoxy-M-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoyl-3,2-siquinoline-2-carboxamide hydrochloride

MN, oh me

M

Me x se OMe

IAS

M IF); h

To a solution of the compound of Auxiliary Example 7 (300 mg, 0.760 mmol), 1-Bos-amino-3-methylaminopropane (286 mg, 1.52 mmol) and NOVI (206 mg, 1.52 mmol) in DMF (10 ml) was added MUZSO (290 mg, 1.52 mmol) while cooling on ice, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate. The extracts were combined, washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluent; ethyl acetate/hexane-2/1) to give tert-butyl 13-CY3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoi3 ,2-c|quinolin-2-yl|carbonylmethyl)amino|propyl/ucarbamate (230 mg) as a non-crystalline white solid.

A solution of the obtained tert-butyl 13-((3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoi3,2-syquinolin-2-ylcarbonylmethyl)amino|Ipropyl)ucarbamate (230 mg) and a 4M ethyl acetate solution of hydrochloride (8 ml) in ethyl acetate (15 ml) were stirred at room temperature for 2 hours.

The resulting precipitate was collected by filtration, washed with diethyl ether and dried under reduced pressure to give the title compound (216 mg, 54 95) as a white powder. "H-NMR (300 MHz, SOSI33) 5: 1.80-2.00 (2H, m), 2.70-2.90 (2H, w), 3.06 (ZH, s), 3.45 -3.60 (2H, m), 3.89 (ZH, s), 5.99 (2H, s), 7.35 (1H, t, U-7.5 Hz), 7.48-7, 67 (AN, m), 7.75-7.79 (4H, m), 7.97 (1H, d, U-7.8 Gu), 8.17-8.19 (2H, m).

Example 105

Preparation of 3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-M-piperidin-4-yl-4,5-dihydrothienoic 3,2-syquinoline-2-carboxamide hydrochloride

N

M

N g xx OMme mo her

H

By a procedure similar to that of Example 73, the title compound (222 mg, 57 90) was obtained as a white powder from the compound of Auxiliary Example 7 (300 mg, 0.760 mmol) and 4-amino-1-Boc-piperidine ( 305 mg, 1.52 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.70-1.95 (2H, m), 2.05 (2H, d, 9U-11.1 Hz), 3.04 (2H, t , 9-11.1 Hu), 3.29 (2H, d, 9U-14.7 Hu), 4.03-4.12 (4H, m), 6.00 (2H, s), 7.35 (1H, t, 957.5 Gu), 7.49 (1H, d, U-8.4 Hz), 7.59-7.67 (ZH, m), 7.77 (1H, t, 9U- 7.5 Hz), 7.90 (1H, d, 9U-7.2 Hz), 8.05 (1H, dd, 9-81, 1.2 Hz), 8.18 (2H, d, 9U- 7.5 Hz), 8.70-8.85 (2H, w).

Example 106

Preparation of M-(2-hydroxyethyl)-3-methoxy-M-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoi3,2-sequinoline-2-carboxamidoone -

M, in Me with OMe

Mo x

By a procedure similar to that of Example 25, the title compound (1.16 g, 68 95) was obtained as white crystals from the compound of Auxiliary Example 7 (1.50 g, 3.80 mmol) and

M-methyl-2-aminoethanol (428 mg, 5.70 mmol). "H-NMR (300 MHz, SOSI»z) 5: 3.00-3.10 (1H, w), 3.21 (3H, s), 3.65-3.80 (2H, w), 3 ,80-4.00 (2H, w), 4.04 (ZH, s), 5.86 (2H, s), 7.03 (1H, d, U-8.4 Gu), 7.26 ( 1H, t, 957.5 Gu), 7.47 (1H, td, 9U-7.8, 1.5 Hz), 7.53-7.59 (2H, m), 7.65-7.71 (1H, m), 7.83 (1H, dd, 9U-9.0, 1.2 Hz), 8.10-8.13 (2H, m).

Example 107

Preparation of /-M-(C1-(2-hydroxyethyl)piperidin-2-yl|methyl)-3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno|3, 2-quinoline-2-carboxamide ve,

Ma,

N g x OoMe

Sea

By a procedure similar to that of Example 101, the title compound (29 mg, 29 95) was obtained as a white powder from the compound of Example 74 (100 mg, 0.19 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.20-1.50 (ZH, m), 1.50-1.80 (ZH, m), 2.27 (1H, t, U- 9.5 Hz), 2.35-2.60 (ZH, m), 2.75-2.90 (1H, m), 2.95 (2H, d, 9U-12.0 Gu), 3, 45-3.60 (4H, m), 4.44 (1H, t, U-5.4 Hz), 6.00 (2H, s), 7.35 (1H, t, 9-7.5 Gu ), 7.49 (1H, d, U-8.4 Hz), 7.57 (IN, d, 9-7.2 Hu), 7.64 (2H, t, 9U-7.5 Hu), 7.77 (1H, t, 9U-7.5 Hz), 8.05 (1H, d, 9-7.2 Hz), 8.10 (1H, t, U-4.2 Hz), 8, 18 (2H, d, 9U-7.2 Hz).

Example 108

Preparation of M-P1-(2-hydroxyethyl)piperidin-4-yl|-3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoyl3,2-syquinoline-2-carboxamide ra

M

AND

Zh sh- OoMe m" o r:

By a procedure similar to that of Example 101, the title compound (41 mg, 27 U) was obtained as a white powder from the compound of Example 105 (150 mg, 0.29 mmol). "H-NMR (300 MHz, DMSO-α) 5: 1.55-1.75 (2H, m), 1.84 (2H, d, 9U-9.6 Hz), 2.18 (2H, t , U-10.2 Hz), 2.37-2.44 (2H, m), 2.77 (2H, d, 9-10.8 Gu), 3.46-3.52 (2H, m) , 3.75-3.85 (1H, m), 4.04 (ZH, s), 4.38 (1H, t, U-5.4

Hz), 6.00 (2H, s), 7.35 (1H, t, U-7.5 Gu), 7.49 (1TN, d, U-8.4 Hz), 7.57 (1H, dd, 9U-7.2, 1.5 Hz), 7.64 (2H, t, 9U-7.5 Hz), 7.71-7.80 (2H, m), 8.05 (1H, dd , 9U-7.2, 1.2 Hz), 8.16-8.19 (2Н, m).

Example 109

Preparation of M-(3-hydroxy-2,2-dimethylpropyl)-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrroloyi3,2 -c|quinoline-2-carboxamide

YAZHZ- Kon / about, A-E-Me

Me 2-X Me x n

SCHE wai OMe vh for o.

What?

By a procedure similar to that of Example 25, the title compound (190 mg, 62 95) was obtained as a white powder from the compound of Auxiliary Example 28 (200 mg, 0.512 mmol) and 3-amino-2,2-dimethyl- 1-propanol (66.4 mg, 0.644 mmol). "H-NMR (300 MHz, DMSO-α) is: 0.88 (6H, s), 3.22-3.24 (4H, m), 4.02 (ZN, s), 4.34 (ZN , s), 4.78 (1H, t, 3-8.3 Hz), 5.98 (2H, s), 7.29-7.40 (2H, m), 7.45-7.51 ( 1H, m), 7.63 (2H, t, U-7.5 Hz), 7.73-7.79 (1H, m), 8.10- 8.19 (ZH, m), 8.38 (1H, dd, 9U-8.4, 1.2 Hz).

Example 110

Preparation of M-(3-hydroxy-2,2-dimethylpropyl)-3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoi3,2-syquinoline-2-carboxamidoone e g sia OoMe mo r

By a procedure similar to that of Example 25, the title compound (251 mg, 69 95) was obtained as white crystals from the compound of Auxiliary Example 7 (300 mg, 0.76 mmol) and 3-amino-2,2- dimethyl-1-propanol (118 mg, 1.14 mmol). "H-NMR (300 MHz, SOSI") 6: 0.89 (6H, s), 3.25-3.35 (AN, m), 4.04 (ZH, s), 4.99 (1H, t, 9-48 Hz), 6.00 (2H, s), 7.35 (1TN, t, 9U-7.5 Hz), 7.49 (1H, d, U-8.4 Hz), 7 .57 (1H, dd, 9-7.2, 1.2 Hz), 7.64 (2H, t, 9-7.5 Gu), 7.77 (IN, t, U9-7.5 Hz) , 8.05 (1H, dd, 9U-7.2, 1.2 Hz), 8.16-8.19 (2H, m), 8.29 (1H, t, 9U-5.7 Hz).

Example 111

Preparation of M-|1-(2-hydroxyethyl)piperidin-4-yl|-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H- pyrrolo|Z,2-c|quinoline-2-carboxamide hydrochloride an yam na

Mmm,

OM and what tr what and about her

I sh

To a solution of the compound of Example 79 (150 mg, 0.290 mmol) in ethyl acetate (4 ml)/ethanol (6 ml) was added

AM solution of hydrochloride in ethyl acetate (80.0 μl). The resulting residue was collected by filtration, washed with ethyl acetate and dried under reduced pressure to give the title compound (72 mg, 45 95) as a white powder. "H-NMR (300 MHz, DMSO-av) 6: 1.88-2.20 (4H, w), 3.05-3.65 (6H, w), 3.74-3.82 (2H, w), 3.90-4.15 (4H, w), 4.28 (ZH, s), 5.30-5.45 (1H, m), 5.98 (2H, s), 7.29-7 .40 (2H, m), 7.46-7.51 (1H, m), 7.64 (2H, t, 9U-7.5 Hz), 7.76 (IN, t, U-7.4 Hz), 8.09-8.19 (ZH, m), 8.37 (1H, d, 9U-7.5 Gu), 9.75-10.10 (IN, w).

Example 112

Preparation of M-(2-(diethylamino)ethyl|-3-methoxy--M-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoyl-3,2-siquinoline-2-carboxamide hydrochloride

ME. iv) and-

M,

X Me with OMe

Ministry of Emergency Situations

By a procedure similar to that of Example 30, the title compound (289 mg, 82 95) was obtained as a white powder from the compound of Auxiliary Example 7 (330 mg, 0.65 mmol) and M,M-diethyl-M' -methylethylenediamine (149 mg, 1.14 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.20-1.40 (6H, w), 3.10-3.40 (6H, m), 3.58 (ZH, s), 3 .84-3.90 (5H, m), 5.99 (2H, s), 7.35 (1H, t, 9U-7.5 Hz), 7.49 (1H, d, U-8.4 Gu), 7.56 (1H, dd, 9U-7.2, 1.2 Gu), 7.60-7.67 (2H, m), 7.77 (IN, t, 9-7.5 Hz ), 7.97 (1H, dd, 9U-7.2, 1.2 Hz), 8.16-8.19 (2H, m), 10.35-10.60 (1H, w).

Example 113

Preparation of 3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-M-K2A)-piperidin-2-ylmethyl-4,5-dihydrothienoyl3,2-siquinoline-2-carboxamide hydrochloride

N

M

In the same s OoMe that NS rya

By a method similar to that given in Example 73, the title compound (166 mg, 60 95) was obtained as a white powder from the compound of Auxiliary Example 7 (200 mg, 0.51 mmol) and (K)-2-aminomethyl- 1-M-Boc-piperidine (163 mg, 0.76 mmol). "H-NMR (300 MHz, DMSO- av) 5: 1.40-1.95 (6H, m), 2.75-3.00 (1H, m), 3.25 (2H, d, 9U- 10.8 Hz), 3.49-3.57 (IN, m), 3.63-3.70 (1Н, m), 4.07 (ЗН, s), 6.01 (2Н, s), 7.36 (1TN, t, 9U-7.5 Gu), 7.50 (IN, d, U-8.7 Gu), 7.57- 7.67 (ZN, m), 7.77 (IN , t, U-7.5 Hz), 8.06 (1Н, dd, 9У-7.2, 1.2 Hz), 8.16-8.19 (2Н, m), 8.27 (1Н, t, U-6.0 Gu), 8.70-8.90 (2H, m).

Example 114

Preparation of M-(2-hydroxy-2-methylpropyl)-3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoi3,2-sequinoline-2-carboxamidon o;- |- Me

M me

N g sn OoMe

M (o) ri

By a procedure similar to that of Example 73, the title compound (108 mg, 47 95) was obtained as white crystals from the compound of Auxiliary Example 7 (200 mg, 0.51 mmol) and 1-amino-2-methyl- 2-propanol (68 mg, 0.76 mmol). "H-NMR (300 MHz, DMSO-av) 6: 1.16 (6H, s), 3.31 (2H, s), 4.06 (ZH, s), 4.77 (1H, s), 6.00 (2H, s), 7.35 (IN, t, 9-7.5 Hz), 7.50 (1H, d, U-8.4 Gu), 7.57-7.67 (ЗН , m), 7.77 (1H, t, 9U-7.5 Hz), 7.98 (1H, t, U-2.4 Gu), 8.05 (1H, d, 9U-7.8 Hz ), 8.18 (2H, d, 9U-7.2 Gu).

Example 115

Preparation of 3-methoxy-M-methyl-M-12-((1-methylethyl)amino|ethyl)-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoi3,2-siquinoline- 2-carboxamide hydrochloride goes

N

1 o'clock in the morning

M x Me not with OoMme

M (o; p:

To a solution of the compound of Example 103 (130 mg, 0.27 mmol), acetone (155 mg, 2.67 mmol), and acetic acid (0.1 mL) in THF (5 mL) was added sodium triacetoxyborohydride (113 mg, 0.54 mmol), and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate. The extracts were combined, washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure.

The residue was purified by chromatography on amino silica gel (eluate; ethyl acetate) to give a colorless oil (0.09 g). To a solution of the obtained colorless oil in ethyl acetate (5 ml) was added

AM solution of hydrochloride in ethyl acetate (0.1 ml). The resulting residue was collected by filtration, washed with ethyl acetate and dried under reduced pressure to give the title compound (73.0 mg, 52 95) as a white powder. "H-NMR (300 MHz, DMSO-α) 6: 1.15-1.35 (6Н, w), 3.05-3.25 (5Н, m), 3.30-3.40 (1Н, m), 3.76 (2Н, pc, 3-6.6 Hz), 3.90 (ЗН, s), 5.99 (2Н, s), 7.35 (1Н, t, 9U-7.5 Gu), 7.49 (1H, t, 9U-8.1 Gu), 7.56 (1H, dd, 9U-7,2,1,2

Gu), 7.60-7.67 (2H, m), 7.77 (1H, t, 9U-7.5 Hz), 7.98 (1H, dd, U-7.2, 1.2 Hz ), 8.16-8.19 (2H, m), 8.50-8.80 (2H, shsh).

Example 116

Preparation of 3-methoxy-M-methyl-M-[3-(1-methylethyl)amino|propyl)-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoic acid]3,2-siquinoline- 2-carboxamide hydrochloride

Me )-me

M o ed,

M,

Meh shhhh- OoMe

M Ge) on y

By a procedure similar to that of Example 115, the title compound (118 mg, 73 95) was obtained as a white powder from the compound of Example 104 (150 mg, 0.30 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.10-1.35 (6H, w), 1.85-2.05 (2H, w), 2.70-3.00 (2H, shu, 3.07 (ЗН, с), 3.20-3.40 (1Н, m), 3.45-3.60 (2Н, m), 3.90 (ЗН, с), 5.99 ( 2H, s), 7.35 (1H, t, 97.5 Hz), 7.49 (1H, d, U-8.4

Hz), 7.56 (1H, dd, 9-6.9, 1.2 Hz), 7.62-7.67 (2H, m), 7.77 (1H, t, 9U-7.5 Gu ), 7.97 (1H, dd, 9U-7.2, 1.2 Gu), 8.16-8.19 (2H, m), 8.65-8.80 (2H, w).

Example 117

Preparation of M-(2-(ethyl(2-hydroxyethyl)amino|ethyl)-3-methoxy-M-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoi|3, 2-c|quinoline-2-carboxamide hydrochloride i- On m (o) i-

M

Me ih is not yet OMe

Mm7to ri

Methanesulfonyl chloride (279 mg, 2.44 mmol) was added to a solution of the compound of Example 106 (1.0 g, 2.21 mmol) and triethylamine (269 mg, 2.66 mmol) in dichloromethane (20 mL) while cooling on ice, and the mixture stirred at room temperature for 18 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure to obtain M-(2-chloroethyl)-3-methoxy-M-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4 ,5-dihydrothieno-3,2-c|quinoline-2-carboxamide (1.01 g), in the form of a white non-crystalline solid.

A solution of the obtained M-(2-chloroethyl)-3-methoxy-M-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoyl3,2-quinoline-2-carboxamide (200 mg , 0.43 mmol), M-ethylaminoethanol (228 mg, 2.55 mmol), diisopropylethylamine (330 mg, 2.55 mmol) and sodium iodide (64 mg, 0.43 mmol) in 1-butanol (5 mL) stirred at 110 "C for 18 hours. The reaction mixture was diluted with a saturated solution of sodium hydrogen carbonate and extracted with ethyl acetate. The extracts were combined, washed with a saturated saline solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on amino silica gel (eluate; from ethyl acetate to ethyl acetate/methanol-20/1), obtaining M-/2-(ethyl(2-hydroxyethyl)amino|ethyl)-3-methoxy-M-methyl-4-oxo-5-(2-oxo-2 -phenylethyl)-4,5-dihydrothienoi|3,2-s|quinoline-2-carboxamide (0.08 g) in the form of a non-crystalline solid of white color. "H-NMR (300 MHz, SOSI»v) 6: 1 ,00-1.15 (0.75N, shu, 1.20-1.35 (2.25N, m), 2.20-2.90 (4N, m), 3.16 (0.75N, c), 3.20 (2, 25Н, с), 3.50-3.95 (6Н, m), 4.02-4.04 (ЗН, m), 5.85 (2Н, с), 7.03 (1Н, d, U- 8.4 Hz), 7.23-

7.28 (IN, m), 7.45 (1H, t, 9U-7.5 Hz), 7.55 (2H, t, 9-7.5 Hz), 7.64-7.69 (1H , m), 7.80-7.84 (1H, m), 8.09-8.12 (2H, m).

A 4M solution of hydrochloride in ethyl acetate (0.1 ml) was added to a solution of the obtained white non-crystalline solid in ethyl acetate (5 ml). The resulting residue was collected by filtration, washed with ethyl acetate and dried under reduced pressure to give the title compound (7 mg, 5 95) as a white powder.

Example 118

Preparation of M-(trano-4-hydroxycyclohexyl)-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrroloyl-3,2-c|quinoline -2-carboxamide en m,

C)

OHM

M ich N trans co

Max) o) same sh

By a procedure similar to that of Example 25, the title compound (230 mg, 95 95) was obtained as a white powder from the compound of Auxiliary Example 28 (200 mg, 0.512 mmol) and trans-4-aminocyclohexanol (74.2 mg , 0.644 mmol). "H-NMR (300 MHz, DMSO-α) 5: 1.22-1.44 (4H, m), 1.83-1.92 (4H, m), 3.40-3.55 (1H, w), 3.68-3.85 (IN, w), 3.96 (ZN, s), 4.30 (ZN, s), 4.57 (1H, d, U-4.2 Gu), 5.96 (2H, s), 7.28-7.38 (2H, m), 7.44-7.50 (1H, m), 7.63 (2H, t, U9-7.5 Hz) , 7.73-7.79 (2H, m), 8.15-8.18 (2H, m), 8.36 (1H, dd, 9U-8.3, 1.1 Hz).

Example 119

Preparation of M-(1-benzylpiperidin-4-yl)-3-methoxy-5-(4-methoxybenzyl)-4-oxo-4,5-dihydrothieno-3,2-syquinoline-2-carboxamide

M u shk, y g i OoMe

HIM (oh; oh

By a method similar to that given in Example 25, the title compound (1.17 g, 82 95) was obtained as white crystals from the compound of Auxiliary Example 13 (1.0 g, 2.52 mmol) and 4-amino- 1-benzylpiperidine (720 mg, 3.78 mmol). "H-NMR (300 MHz, DMSO -av) 6: 1.55-1.75 (2H, m), 1.80-1.95 (2H, w d), 2.17 (2H, t, U -10.2 Gu), 2.65- 2.80 (2H, w d), 3.50 (2H, s), 3.70 (ZH, s), 3.80-3.90 (1H, w )y, 4.08 (ZH, s), 5.53 (2H, w s), 6.85-6.88 (2H, m), 7.20 (2H, d, 9U-8.7 Hz) , 7.25-7.34 (5H, m), 7.49-7.56 (2H, m), 7.74 (1H, d, U-7.8 Hz), 8.00 (1H, dd , uU-8,1,1,2

Gu).

Example 120

Preparation of M-(3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno|3,2-c)quinolin-2-yl|carbonyl)-M-methylglycine ethyl ester at 00 А сОЖж

M, 8 Me x s OmMe

Mo

WITH

By a procedure similar to that of Example 25, the title compound (400 mg, 91 95) was obtained as a white solid from the compound of Example 7 (350 mg, 0.89 mmol) and sarcosine ethyl ester hydrochloride (204 mg , 1.33 mmol). "H-NMR (300 MHz, SOSIz) 5: 1.24-1.35 (ZH, m), 3.19 (1.2H, w s), 3.24 (1.8H, s), 3, 98 (1.2N, w s), 4.08 (1.8N, s), 4.15-4.30 (AN, m), 5.86 (2N, s), 7.03 (1N, d , 9-8.7 Gu), 7.24-7.29 (1H, m), 7.43-7.49 (1H, m), 7.53-7.58 (2H, m), 7, 65-7.70 (1H, m), 7.83 (1H, dd, U9-7.8, 1.2 Hz), 8.10-8.13 (2H, m).

Example 121

Preparation of M-(2-(diethylamino)ethyl|-3-methoxy-M-methyl-4-oxo-4,5-dihydrothieno|3,2-c|quinoline-2-carboxamide

ЕЙ h

M-E (in) --

M,

Me x p OMe

M (9) nN

A mixture of the compound of Example 48 (4.10 g, 8.08 mol), trifluoroacetic acid (34 ml) and trifluoromethanesulfonic acid (6.6 ml) was stirred at room temperature for 5 hours and at 80 "C for 2.5 hours. After after cooling, the reaction mixture was concentrated under reduced pressure and ethyl acetate and 1 M aqueous sodium hydroxide were added to the residue. The mixture was extracted with ethyl acetate and the extract was successively washed with water and saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on amino silica gel (eluate; ethyl acetate/hexane-1/2) to give the title compound (1.50 g, 48 95) as a white powder." H-NMR (300 MHz, DMSO-α) 6: 0.70 -1.10 (6H, w), 2.20-2.70 (6H, w), 3.05 (ЗН, с), 3.40-3.60 (2Н, w), 3.91 (ЗН , c), 7.21-7.26 (1H, m), 7.38-7.41 (1H, m), 7.49-7.55 (1H, m), 7.82-7.85 (1H, m), 11.75 (1H, s).

Example 122

Preparation of /1(2-PG2-(diethylamino)ethyl)(methyl)carbamoyl)-3-methoxy-4-oxothieno|3,2-c|quinolin-5(4H)-yl|acetic acid k k

M- EE 00000 i K z-k 5th Me sr

ZK about the nose

A solution of the compound of Example 53 (670 mg, 1.41 mmol) and an 8M aqueous solution of sodium hydroxide (1.0 ml) in ethanol (7.0 ml) was stirred at room temperature for 15 hours. The reaction mixture was neutralized with 1M hydrochloric acid and concentrated under reduced pressure. THF was added to the residue and, after filtration, the filtrate was concentrated under reduced pressure to give the title compound (580 mg, 92 95) as a pale yellow solid. "H-NMR (300 MHz, DMSO-α) 6: 1.10-1.35 (6Н, w), 2.70-3.30 (9Н, m), 3.70-3.85 (2Н, w), 3.91 (ZH, s), 5.06 (2H, s), 7.34 (1H, t, U9-7.7 Hz), 7.48 (IN, d, 9U-8.2 Hz), 7.62 (1H, t, 9U-8.2 Hz), 7.94 (1H, d, 9U-7.7 Gu).

Example 123

Preparation of 2-I4-(13-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrole|3,2- syquinoline-2-ylcarbonyl )amino)piperidine-1-yl|-2-oxoethyl acetate

Me o o- t it 0 U

M

Me, her

MORE t OMe

M (c) r:

To a mixture of the compound of Example 77 (200 mg, 0.423 mmol), triethylamine (122 μL, 0.880 mmol), and THF (10 mL) was added acetoxyacetyl chloride (47.3 μL, 0.440 mmol) at 0 °C, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by amino silica gel chromatography (eluate; ethyl acetate) and the resulting solid was recrystallized from ethyl acetate-THF to give the title compound (171 mg, 75 95) as a white powder. "H-NMR (300 MHz, DMSO-α) 6: 1.35-1.70 (2H, m), 1.80-2.00 (2H , m), 2.08 (ЗН, s), 2.80-3.00 (1Н, m), 3.10-3.25 (1Н, m), 3.60-3.80 (1Н, m ), 3.97 (ZH, s), 4.00-4.25 (2H, m), 4.31 (ZH, s), 4.80 (2H, d, 9-1.8 Gu), 5 .97 (2H, s), 7.29-7.39 (2H, m), 7.45-7.50 (1H, m), 7.63 (2H, t, 9-7.5 Hz), 7.73-7.79 (1H, m), 7.98 (1H, d,

U-7.8 Hz), 8.16-8.18 (2H, m), 8.37 (1H, dd, 9U-8.4, 1.2 Hz).

Example 124

Preparation of M-/1-(hydroxyacetyl)piperidin-4-yl|-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo| 3,2-s|quinoline-2-carboxamide about ОН ut

IN

M

Me. N

MORE p OMe

M 8)

WITH

1) A mixture of a solution of the compound of Example 123 (125 mg, 0.218 mmol) and an 8M aqueous solution of sodium hydroxide (1 ml) in THF (2 ml)-ethanol (7 ml) was stirred at room temperature for 2 hours.

The reaction mixture was diluted with water, acidified with EM hydrochloric acid (1.5 ml) and extracted with ethyl acetate. The extracts were combined, washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by amino silica gel chromatography (eluate; ethyl acetate) and the resulting solid was recrystallized from ethyl acetate-THF to give the title compound (59.2 mg, 51 95) as white crystals. "H-NMR (300 MHz, DMSO- av) 6: 1.35-1.65 (2H, m), 1.80-2.00 (2H, m), 2.85-3.00 (1H, m), 3.05-3.25 (1H, m), 3.60-3.75 (1H, m), 3.97 (ZH, s), 4.00-4.30 (AN, m) , 4.31 (ZH, s), 4.51 (1H, t, U-5.3 Hz), 5.97 (2H, s), 7.29-7.39 (2H, m), 7, 48 (1H, t, U-7.6 Hu), 7.63 (2H, t, 9U-7.6 Hz), 7.76 (1TN, t, U-7.4 Hu), 7.95 ( 1H, d, U-8.4 Hu), 8.17 (2H, d, 9U-7.6 Hz), 8.37 (1H, d, 9U-8.1 Hu). 2) The white powder was recrystallized from ethanol-water to give the title compound as white crystals, mp 22420

Example 125

Preparation of tert-butyl 4-(3-methoxy-1,6-dimethyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo|3,2-s| Ipyridine-2-ylcarbonylamino)piperidine-1-carboxylate

Me Me o -Me h-ao

In me, i

My n OoMe

Me Mori

By a procedure similar to that of Example 25, the title compound (315 mg, 72 95) was obtained as a white powder from the compound of Auxiliary Example 35 (290 mg, 0.818 mmol) and 4-amino-1-Boc-piperidine ( 212 mg, 1.06 mmol). "H-NMR (300 MHz, DMSOO-av) 6: 1.29-1.51 (11Н, m), 1.75-1.90 (2Н, m), 2.28 (ЗН, с), 2 .86-3.05 (2H, m), 3.77-3.90 (5H, m), 3.92-4.04 (AN, m), 5.62 (2H, s), 6.58 (1H, s), 7.55-7.66 (ZH, m), 7.73 (1H, d, U-6.6 Hu),

8.11 (2H, d, 9-7.7 Hz).

Example 126

Preparation of 33-methoxy-1,6-dimethyl-4-oxo-5-(2-oxo-2-phenylethyl)-M-piperidin-4-yl-4,5-dihydro-1H-pyrrolo|Y3,2- c|Ipyridine-2-carboxamide hydrochloride

N ul o u

Mi Nei

Me. her

IM x pe OMe

Me IR o r:

To a mixture of the compound of Example 125 (300 mg, 0.559 mmol) and ethyl acetate (4 mL) was added a 4M solution of hydrochloride in ethyl acetate (4 mL), and the mixture was stirred at room temperature for 2 hours.

The resulting solid was collected by filtration and washed with ethyl acetate to give the title compound (240 mg, 91 95) as a white powder. "H-NMR (300 MHz, DMSO-dv) 6: 1.61-1.84 (2H, m), 1.95-2.11 (2H, m), 2.28 (ZH, s), 2 .92-3.12 (2Н, m), 3.20-3.32 (2Н, m), 3.83 (ЗН, с), 3.94-4.15 (4Н, m), 5.62 (2H, s), 6.59 (1H, s), 7.61 (2H, t, U-7.6 Gu), 7.68-7.81 (2H, m), 8.04-8, 19 (2H, m), 8.64 (IN, w s), 8.87 (IN, w s).

Example 127

Preparation of 2-I4-(|3-methoxy-1,6-dimethyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo|3,2- cIpyridine- 2-ylcarbonyl)amino)piperidin-1-yl|-2-oxoethyl acetate

Me 0 0- mo yam shk

Me. eat

M and p OoMe

Me M (c)

H

By a procedure similar to that of Example 123, the title compound (210 mg, 82 95) was prepared as a white powder from the compound of Example 126 (225 mg, 0.476 mmol) and acetoxyacetyl chloride (61.4 μL, 0.571 mmol). "H-NMR (300 MHz, DMSO-dv) 5: 1.26-1.64 (2H, m), 1.78-1.97 (2H, m), 2.09 (ZH, s), 2 .28 (ZH, s), 2.79-2.97 (1H, m), 3.09-3.25 (1H, m), 3.58-3.74 (1H, m), 3.86 (ЗН, с), 3.95-4.20 (5Н, m), 4.79 (2Н, с), 5.62 (2Н, с), 6.58 (1Н, с), 7.55- 7.68 (ZH, m), 7.69-7.78 (1H, m), 8.06-8.15 (2H, m).

Example 128

Preparation of M-P1-«(hydroxyacetyl)piperidin-4-yl|-3-methoxy-1,6-dimethyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H- pyrrolo|3,2-c|Ipyridine-2-carboxamide (o, On u

Me. their

M

M s OoMe

Me M o rya

By a method similar to that given in Example 124, the title compound (156 mg, 85 95) was obtained as a white powder from the compound of Example 127 (200 mg, 0.373 mmol), 8M aqueous sodium hydroxide solution (0.5 ml) , THF (2.5 ml) and ethanol (5 ml). "H-NMR (300 MHz, DMSO-dv) 6: 1.32-1.61 (2H, m), 1.79-1.93 (2H, m), 2.28 (ZH, s), 2 .82-2.98 (1Н, m), 3.04-3.20 (1Н, m), 3.57-3.71 (IN, m), 3.86 (ЗН, с), 3.96 -4.25 (7N, m), 4.50 (1TN, d, U-5.3 Hz), 5.61 (2N, s), 6.58 (1N, s), 7.55-7, 67 (ZH, m), 7.69-7.78 (1H, m), 8.07-8.16 (2H, m).

Example 129

Preparation of tert-butyl 4-(C6b-ethyl-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolyl3,2-c|Ipyridine -2-ylcarbonyl)amino)piperidine-1-carboxylate

Me Me o mZh-Me --o t p,

Me. and

STILL with OMe

E MI o h

By a procedure similar to that of Example 25, the title compound (126 mg, 84 95) was obtained as a white powder from the compound of Auxiliary Example 42 (100 mg, 0.271 mmol) and 4-amino-1-Boc-piperidine ( 70.7 mg, 0.353 mmol). "H-NMR (300 MHz, DMSO-av) 5: 1.18 (ZH, t, 9-7.3 Hz), 1.32-1.51 (11H, m), 1.74-1.89 (2H, m), 2.58 (2H,

Kk, y-7.5 Gu), 2.85-3.04 (2Н, m), 3.77-3.91 (5Н, m), 3.91-4.05 (4Н, m), 5 .59 (2H, s), 6.49 (1H, s), 7.55-7.67 (ZH, m), 7.69-7.79 (1H, m), 8.06-8.16 (2H, m).

Example 130

Preparation of b-ethyl-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-M-piperidin-4-yl-4,5-dihydro-

1H-pyrrolyl3,2-c|Ipyridine-2-carboxamide hydrochloride

Well,

Me and NS

M by OoMe

E MO r

A solution of the compound of Example 129 (115 mg, 0.209 mmol) and a 4M ethyl acetate hydrochloride solution (4 mL) in ethyl acetate (4 mL) was stirred at room temperature for 3 hours. The resulting solid was collected by filtration and washed with ethyl acetate to give the title compound.

Example 131

Preparation of b-ethyl-M-(1-(hydroxyacetyl)piperidin-4-yl|-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro- 1H-pyrrolo|3,2-s|Ipyridine-2-carboxamide o On / 65 me.

AND; n OoMe

Emo ri

To a mixture of the compound of Example 130 (90.0 mg, 0.185 mmol), triethylamine (76.9 μL, 0.555 mmol), and THF (5 mL) was added acetoxyacetyl chloride (23.8 μL, 0.221 mmol) at 0 °C, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography on amino silica gel (eluate; ethyl acetate) and the resulting solid was dissolved in THF (1 .2 ml)-ethanol (2.5 ml). 8M aqueous sodium hydroxide solution (250 μl) was added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water, acidified with 6M hydrochloric acid (0.5 ml) and extracted ethyl acetate. The extracts were combined, washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on amino silica gel (eluate; ethyl acetate/methanol--10/0-9/1) and The precipitated solid was recrystallized from ethyl acetate to give the title compound (61.2 mg, 65 mg) as white crystals. "H-NMR (300 MHz, DMSO-dv) 5: 1.13-1.23 (ZH, m), 1.31-1.59 (2H, m), 1.80-1.94 (2H, m), 2.58 (2H, k,

9-74 Gu), 2.83-2.99 (1Н, m), 3.04-3.21 (1Н, m), 3.59-3.70 (1Н, m), 3.89 (ЗН , s), 3.97-4.26 (7H, m), 4.49 (1H, t, 95.4 Hz), 5.59 (2H, s), 6.49 (1H, s), 7 ,56-7.67 (ZH, m), 7.70-7.78 (1H, m), 8.06-8.15 (2H, m).

Example 132

Preparation of 3-ethoxy-N-(2-hydroxy-2-methylpropyl)-1,6-dimethyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrroloyi3,2 -c|Ipyridine-2-carboxamide on o 0 /-i-Me

Me. i Me that p (schi

Me M (o, vi

By a procedure similar to that of Example 25, the title compound (65.8 mg, 67 95) was obtained as a white powder from the compound of Auxiliary Example 44 (100 mg, 0.271 mmol) and 1-amino-2-methylpropane- 2-ol (31.5 mg, 0.353 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.13 (6H, s), 1.31 (ZH, t, 9-7.0 Hz), 2.28 (ZH, s), 3, 24 (2H, d, 9U-5.5 Hz), 3.90 (ZH, s), 4.35 (2H, k, 9U-7.0 Gu), 4.66 (1TN, s), 5, 61 (2H, s), 6.59 (1H, s), 7.61 (2H, t, U-7.6 Gu), 7.69-7.79 (IN, m), 7.93 (1H , t, U-5.6 Hz), 8.06-8.15 (2Н, m).

Example 133

Preparation of /3-ethoxy-1,6-dimethyl-4-oxo-5-(2-oxo-2-phenylethyl)-M-piperidin-4-yl-4,5-dihydro-1H-pyrrolo|Y3,2 -c|Ipyridine-2-carboxamide hydrochloride

N and o) Her

Me, M

M x what oi

Me Mo r

By a procedure similar to that of Example 73, the title compound (303 mg, 95 95) was obtained as a white powder from the compound of Auxiliary Example 44 (250 mg, 0.679 mmol) and 4-amino-1-Boc-piperidine ( 177 mg, 0.882 mmol). "H-NMR (300 MHz, DMSOO-av) 6: 1.28 (ZH, t, 9U-7.1 Hz), 1.61-1.81 (2H, m), 1.97-2.12 (2Н, m), 2.28 (ЗН, с), 2.94-3.10 (2Н, m), 3.21-3.32 (2Н, m), 3.85 (ЗН, с), 3.97-4.14 (1H, m), 4.34 (2H, k, 9-7.0 Gu), 5.62 (2H, s), 6.59 (1H, s), 7.61 (2H, t, U-7.6 Hu), 7.69-7.81 (2H, m), 8.04-8.17 (2H, m), 8.85 (2H, w s).

Example 134

Preparation of M-(2-hydroxy-2-methylpropyl)-3-methoxy-1,6-dimethyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrroloyi3,2 -c|Ipyridine-2-carboxamide on o 0 /-i-Me

Me M Me "M N x sh- OoMe

Me Mor:

By a procedure similar to that of Example 25, the title compound (201 mg, 84 95) was obtained as a white powder from the compound of Auxiliary Example 35 (200 mg, 0.564 mmol) and 1-amino-2-methylpropane-2- beer (65.4 mg, 0.734 mmol). "H-NMR (300 MHz, DMSO-av) 6: 1.13 (6H, s), 2.29 (ZH, s), 3.24 (2H, d, 9U-5.7 Hz), 3, 89 (ZN, s), 4.02 (ZN, s), 4.65 (1H, s), 5.62 (2H, s), 6.59 (1H, s), 7.56-7.66 (2H, m), 7.69-7.78 (1H, m), 7.85 (1H, t, U-5.7 Hu), 8.06-8.15 (2H, m).

Example 135

Preparation of 3-methoxy-1,6-dimethyl-4-oxo-5-(2-oxo-2-phenylethyl)-M-(1-pyridin-4-ylpiperidin-4-yl)-4,5-dihydro-1H -pyrrolo|3,2-s|Ipyridine-2-carboxamide

M in U im 05

IR me. N

M p OoMe

Me M (c) r:

By a procedure similar to that of Example 25, the title compound (656 mg, 91,906) was obtained as a white powder from the compound of Auxiliary Example 35 (500 mg, 1.41 mmol) and 1-pyridin-4-ylpiperidine- 4-amine (388 mg, 1.55 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.48-1.65 (2H, m), 1.85-1.97 (2H, m), 2.28 (ZH, s), 2 .98-3.14 (2Н, m), 3.77-3.90 (5Н, m), 3.98 (ЗН, с), 4.01-4.15 (1Н, m), 5.61 (2H, s), 6.58 (1H, s), 6.82 (2H, d, 9U-1.5 Hz), 7.56-7.68 (ЗН, m), 7.70-7, 78 (1H, m), 8.05-8.20 (4H, m).

Example 136

Preparation of 3-ethoxy-M-(P1-(hydroxyacetyl)piperidin-4-yl|-1,6-dimethyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H- pyrrolo|3,2-s|Ipyridine-2-carboxamide

8, On /t o i me, y

SCHE pe OB

Me E o ri

To a mixture of the compound of Example 133 (200 mg, 0.423 mmol), triethylamine (122 μL, 0.880 mmol), and THF (10 mL) was added acetoxyacetyl chloride (47.3 μL, 0.440 mmol) at 0 °C, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was diluted with ethyl acetate, washed with water and saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in ethanol (7 ml) and THF (2 ml), and 8M aqueous sodium hydroxide solution (1 ml) was added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water, acidified with 6M hydrochloric acid (1.5 mL), and extracted with ethyl acetate. The extracts were combined, washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography on amino silica gel (eluate; ethyl acetate) and the resulting solid was recrystallized from ethyl acetate-hexane to give the title compound (102 mg, 65 95) in the appearance of white crystals. "H-NMR (300 MHz, DMSOO-av) 6: 1.25 (ZH, t, 9U-7.1 Hz), 1.531-1.57 (2H, m), 1.82-1.96 (2H , m), 2.28 (ЗН, с), 2.80-2.95 (1Н, m), 3.03-3.19 (1Н, m), 3.87 (ЗН, с), 3, 95-4.13 (ZH, m), 4.18-4.28 (1H, m), 4.34 (2H, k, 9U-7.0

Hz), 4.50 (IN, t, U-5.4 Hz), 5.61 (2H, s), 6.58 (1H, s), 7.55-7.78 (AN, m), 8.06-8.14 (2H, m).

Example 137

Preparation of M-(1-(hydroxyacetyl)piperidin-4-yl|-1,6-dimethyl-4-oxo-5-(2-oxo-2-phenylethyl)-3-propoxy-4,5-dihydro-1 H -pyrrolo|3,2-s|Ipyridine-2-carboxamide (o)one,

M me. N

Lk se (6) -

Me M (o) Me ex

By a procedure similar to that of Example 25, the title compound (45.2 mg, 33 95) was obtained as a white powder from the compound of Auxiliary Example 46 (100 mg, 0.262 mmol), 2-(4-aminopiperidine-1 -yl)-2-oxoethanol hydrochloride (61.1 mg, 0.314 mmol) and triethylamine

(43.5 μl, 0.314 mmol). "H-NMR (300 MHz, DMSO-av) 6: 0.92 (ZH, t, 9-74 Hu), 1.22-1.53 (2H, m), 1.60-1.75 (2H , m), 1.85-1.95 (2Н, m), 2.27 (ЗН, с), 2.77-2.92 (1Н, m), 3.00-3.17 (1Н, m ), 3.60-3.74 (1H, m), 3.86 (ZH, s), 3.95-4.13 (ZH, m), 4.25 (ZH, t, U-6.7 Hz), 4.50 (1H, t, 9U-5.4 Hz), 5.62 (2H, s), 6.57 (1H, s), 7.55-7.67 (ZH, m), 7.69-7.78 (1H, m), 8.05-8.16 (2H, m).

Example 138

Preparation of 3-ethoxy-M-(1-(2-hydroxyethyl)piperidin-4-yl|-1,6-dimethyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro- 1H-pyrrolo|3,2-s|Ipyridine-2-carboxamide ray in 6 me, and

WHAT WITH OB

Me Mori

By a procedure similar to that of Example 79, the title compound (78.5 mg, 57 95) was obtained as a white powder from the compound of Example 133 (135 mg, 0.277 mmol) and 2-bromomethanol (58.9 μl, 0.832 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.28 (ZH, t, 9U-7.1 Hu), 1.39-1.57 (2H, m), 1.78-1.91 (2H, m), 2.09-2.22 (2H, m), 2.28 (ZH, s), 2.38 (2H, t, U-6.3 Hu), 2.67-2, 81 (2H, t, ), 3.48 (2H, k, U-6.2 Gu), 3.70-3.83 (1H, m), 3.87 (ZH, s), 4.29- 4.41 (ZH, m), 5.61 (2H, s), 6.58 (1H, s), 7.56-7.68 (ZH, m), 7.70-7.78 (1H, m), 8.06-8.15 (2H, m).

Example 139

Preparation of 3-ethoxy-b-ethyl-M-|/1-(hydroxyacetyl)piperidin-4-yl|-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro -1H-pyrrolo|3,2-s|Ipyridine-2-carboxamide o onum ka,

Me. M

M i on OB

EI M (o; ri 1) To a solution of the compound of Auxiliary Example 48 (74.0 mg, 0.194 mmol), 2-(4-aminopiperidin-1-yl)-2-oxoethanol hydrochloride (49.1 mg, 0.252 mmol), To NOVI (39.2 mg, 0.290 mmol) and triethylamine (34.9 μL, 0.252 mmol) in DMF (3 mL) was added MUZSO (55.6 mg, 0.290 mmol) under ice-cooling and the mixture was stirred at room temperature for 15 hours The reaction mixture was diluted with water and extracted with ethyl acetate. The extracts were combined, washed with water and saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by amino silica gel chromatography (eluate; ethyl acetate) and the resulting solid was recrystallized from ethyl acetate to give the title compound (61.2 mg, 60 95) as white crystals. "H-NMR (300 MHz, DMSO-α) 5: 1.13-1.29 (6Н, m), 1.32-1.56 (2Н, m), 1.83-1.96 (2Н, m), 2.57 (2H, k, 9-74 Gu), 2.80-2.94 (1H, m), 3.04-3.19 (1H, m), 3.59-3.72 (1Н, m), 3.90 (ЗН, с), 3.95-4.14 (ЗН, m), 4.17-427 (IN, m), 4.34 (2Н, k, 9U-7 .2 Hz), 4.51 (1H, t, U-5.4 Hz), 5.59 (2H, s), 6.49 (1H, s), 7.56-7.65 (2H, m ), 7.66-7.77 (2H, m), 8.07-8.14 (2H, m). 2) White crystals were recrystallized from ethanol-water, obtaining the title compound in the form of white crystals. Melting point 20420

Example 140

Preparation of M-P-(hydroxyacetyl)piperidin-4-yl|-1,6-dimethyl-4-oxo-5-(2-oxo-2-phenylethyl)-3-(2,2,2-trifluoroethoxy)-4 ,5-dihydro-1H-pyrrolo|3,2-s|Ipyridine-2-carboxamide o OH ul 0 U

Me. her

M more (0) E she me CM then E

H

1) To a solution of the compound of Auxiliary Example 50 (70.0 mg, 0.166 mmol), 2-(4-aminopiperidin-1-yl)-2-oxoethanol hydrochloride (42.0 mg, 0.216 mmol), NEW (33.6 mg , 0.249 mmol) and triethylamine (29.9 μL, 0.216 mmol) in DMF (3 mL) was added MUZSO (55.6 mg, 0.290 mmol) while cooling on ice, and the mixture was stirred at room temperature for 15 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The extracts were combined, washed with water and saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by amino silica gel chromatography (eluate; ethyl acetate) and the resulting solid was recrystallized from ethyl acetate to give the title compound (51.3 mg, 55 95) as white crystals. "H-NMR (300 MHz, DMSO-α) 6: 1.22-1.50 (2H, m), 1.81-1.94 (2H, m), 2.29 (ZH, s), 2 .74-2.91 (1H, m), 3.01-3.16 (1H, m), 3.63-3.75 (1H, m), 3.683 (ZH, s), 3.95-4 .13 (ZH, m), 4.20-4.32 (1H, m), 4.53 (1H, t, U-5.5

Hz), 5.06 (2H, k, U-9.3 Hz), 5.65 (2H, s), 6.64 (1H, s), 7.51 (1H, d, 9U-7.7 Hz), 7.57-7.66 (2H, m), 7.70-7.79 (IN, m), 8.07-8.15 (2H, m). 2) The white crystals were recrystallized from ethanol-water to give the title compound as white crystals. Melting point 13220

Example 141

Preparation of 3-ethoxy-M-|/1-(hydroxyacetyl)piperidin-4-yl|-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-6-propyl-4,5-dihydro -1 H-pyrrolo|3,2-s|Ipyridine-2-carboxamide

(o) On ud 0 U

Me, uh

MORE ABOUT

Me M (c) rya

To a solution of the compound of Auxiliary Example 57 (200 mg, 0.504 mmol), 2-(4-aminopiperidin-1-yl)-2-oxoethanol hydrochloride (128 mg, 0.656 mmol), NOVI (102 mg, 0.757 mmol) and triethylamine (90 .8 μL, 0.656 mmol) in DMF (5 mL) was added M/UZSO (145 mg, 0.757 mmol) under ice-cooling and the mixture was stirred at room temperature for 15 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The extracts were combined, washed with water and saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by amino silica gel chromatography (eluate; ethyl acetate) and the resulting solid was recrystallized from THF-ethyl acetate to give the title compound (224 mg, 83,905) as white crystals. "H-NMR (300 MHz, DMSO-α) 5: 0.93 (ZN, t, 97.3 Hz), 1.25 (ZN, t, 97.1 Hz), 1.31-1.66 ( AN, m), 1.84-1.95 (2Н, m), 2.51-2.59 (2Н, m), 2.81-2.95 (1Н, m), 3.04-3, 18 (1Н, m), 3.61-3.71 (1Н, m), 3.89 (ЗН, с), 3.96- 4.14 (ЗН, m), 4.18-4.27 ( 1H, m), 4.33 (2H, k, 9U-7.0 Gu), 4.51 (1H, t, U-5.1 Hz), 5.55 (2H, s), 6.51 ( 1H, c), 7.56-7.77 (AN, m), 8.08-8.14 (2H, m).

Example 142

Preparation of b-ethyl-3-(2-fluoroethoxy)-IM-(1-(hydroxyacetyl)piperidin-4-yl|-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4, 5-dihydro-1 H-pyrrolo|3,2-s|Ipyridine-2-carboxamide (o) he in b

Me. their

M x s (o; -

EMO E r

To a solution of the compound of Auxiliary Example 59 (202 mg, 0.504 mmol), 2-(4-aminopiperidin-1-yl)-2-oxoethanol hydrochloride (128 mg, 0.656 mmol), NOVI (102 mg, 0.757 mmol) and triethylamine (90 .8 μL, 0.656 mmol) in DMF (5 mL) was added MUZSO (145 mg, 0.757 mmol) while cooling on ice, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The extracts were combined, washed with water and saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by amino silica gel chromatography (eluate; ethyl acetate) and the resulting solid was recrystallized from THF-ethyl acetate to give the title compound (219 mg, 80 95) as white crystals. "H-NMR (300 MHz, DMSO-av) 5: 1.19 (ZH, t, 9U-7.4 Gu), 1.26-1.48 (2H, m), 1.87 (2H, s ), 2.59 (2H, k, 97.4 Hz), 2.76-2.91 (1H, m), 3.01-3.17 (1H, m), 3.57-3.73 ( 1H, m), 3.92 (ZH, s), 3.97-4.13 (ZH, m), 4.18-4.32 (IN, m), 4.45-4.81 (5H, m), 5.59 (2Н, с), 6.49-6.56 (1Н, m), 7.55-7.66 (ЗН, m), 7.69-7.78 (1Н, m) , 8.06-8.16 (2H, m).

Example 143

Preparation of β-ethyl-N-(|1-(hydroxyacetyl)piperidin-4-yl|-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-3-(2,2,2 -trifluoroethoxy)-4,5-dihydro-1H-pyrrolo|3,2-s|Ipyridine-2-carboxamide

UN t o u / me, M

STILL p OO is ish

EOM To E r: 1) To a solution of the compound of Auxiliary Example 61 (230 mg, 0.527 mmol), 2-(4-aminopiperidin-1-yl)-2-oxoethanol hydrochloride (133 mg, 0.685 mmol), NEW (107 mg, 0.791 mmol) and triethylamine (95.0 μL, 0.685 mmol) in DMF (4 mL) was added MU/ZSO (152 mg, 0.791 mmol) under ice-cooling and the mixture was stirred at room temperature for 15 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The extracts were combined, washed with water and saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on amino silica gel (eluate; ethyl acetate/hexane-1/3-1/0) and the resulting solid was recrystallized from ethyl acetate-hexane to give the title compound (146 mg, 48 95) as white crystals. "H-NMR (300 MHz, DMSOO-av) 6: 1.13-1.49 (5Н, m), 1.82-1.94 (2Н, m), 2.59 (2Н, k, 9- 7.2 Hz), 2.76-2.88 (IN, m), 3.02-3.15 (1Н, m), 3.64-3.75 (1Н, m), 3.86 (ЗН , c), 3.96-4.16 (ZH, m), 4.20-4.33 (1H, m), 4.53 (1H, t, y-5.4 Hz), 5.05 ( 2H, k, U-9.3 Hz), 5.63 (2H, s), 6.54 (1H, s), 7.51 (1H, d, 9-7.7 Hz), 7.61 ( 2H, t, U-7.6 Gu), 7.70-7.78 (1H, m), 8.08-8.14 (2H, m). 2) White crystals were recrystallized from ethanol-water, obtaining the indicated the title compound as white crystals, melting point: 15920

Example 144

Preparation of /- M-(2-(diethylamino)ethyl|-3-methoxy-M-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5,6,7,8,9- of hexahydrothienoi3,2-siquinoline-2-carboxamide

Hey,

M-EI 0000

M,

Meh pe OoMe

More

By a procedure similar to that of Example 25, the title compound (54.0 mg, 28 95) was obtained as a colorless oil from the compound of Auxiliary Example 66 (150 mg, 0.377 mmol) and M,M-diethyl-M' -methylethane-1,2-diamine (79.3 μL, 0.490 mmol). "H-NMR (300 MHz, DMSOO-av) 6: 0.74-1.05 (6Н, m), 1.67-1.85 (4Н, m), 2.19-2.65 (TON, m), 3.03 (ZH, s), 3.40-3.56 (2H, m), 3.82 (ZH, s), 5.65 (2H, s), 7.61 (2H, t , 9-7.6 Hz), 7.70-7.78 (1H, m), 8.07-8.16 (2H, m).

Example 145

Preparation of M-(2-(diethylamino)ethyl|-3-ethoxy-M,b-dimethyl-4-oxo-4,5-dihydrothieno|3,2-c|pyridine-2-carboxamide

ЕЙ h

M--EII about -i-

M, 5 Me x on OEi

Me M o n

A mixture of the compound of Auxiliary Example 70 (2.50 g, 6.51 mmol), 6M hydrochloric acid (15 ml) and

DMF (15 ml) was stirred for 15 hours under reflux. After cooling, the reaction mixture was concentrated under reduced pressure and water (20 ml) was added to the residue. The mixture was neutralized with saturated sodium bicarbonate solution and extracted with ethyl acetate.

The extract was successively washed with water and saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography on amino silica gel (eluate; ethyl acetate) to give the title compound (568 mg, 24 90) as a colorless oil. "H-NMR (300 MHz, DMSO-α) 5: 0.70-1.05 (6Н, m), 1.21 (ЗН, t, 9-7.0 Hu), 2.21 (ЗН, s ), 2.25-2.65 (6Н, m), 3.01 (ЗН, с), 3.40-3.55 (2Н, m), 4.13 (2Н, k, 9-7.0 Hz), 6.54 (1H, s), 11.41 (1H, s).

Example 146

Preparation of M-(2-(diethylamino)ethyl|-3-ethoxy-M,b-dimethyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno]3,2-c|Ipyridine- 2-carboxamide

EY

M-E 00. -

M,

Kh Me n OB

Me Mori

A mixture of the compound of Example 145 (300 mg, 0.821 mmol), phenacyl bromide (196 mg, 0.985 mmol), potassium carbonate (272 mg, 1.97 mmol), and DMF (5 mL) was stirred at 60 °C for 15 h. After cooling, the mixture was diluted with water (10 ml) and extracted with ethyl acetate. The extract was successively washed with water and saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on amino silica gel (eluate; ethyl acetate/hexane - from 1/9 to 10 /0), yielding the title compound (51.2 mg, 13 95) as a colorless oil. "H-NMR (300 MHz, DMSO-α) 6: 0.70-1.05 (6H, m), 1.15-1.20 (ZH, m), 2.25-2.65 (9H, m), 3.02 (ZH, w s), 3.40-3.55 (2H, m), 4 .05 (2H, k, 9U-6.9 Hz), 5.66 (2H, s), 6.80-6.81 (1TN, m), 7.62 (2H, t, 97.7 Gu, 7.72-7.78 (IN, m), 8.10-8.13 (2H, m).

Example 147

Preparation of M-(2-(diethylamino)ethyl)|-3-ethoxy-M,b,7-trimethyl-4-oxo-4,5-dihydrothieno|3,2-c|Ipyridine-2-carboxamide

Eh

M-EI (c) и-

M

IN

5 x Me

Me a OB me M (c) nN

By a procedure similar to that of Example 145, the title compound (60 mg, 29 95) was obtained as a white solid from the compound of Sub-Example 74 (220 mg, 0.55 mmol). "H-NMR (300 MHz, DMSO-α) 6: 0.80-1.10 (6Н, m), 1.37 (ЗН, t, 9-6.9 Hz), 2.17 (ЗН, s ), 2.41 (ZH, s), 2.48-2.73 (6H, m), 3.17 (ZH, s), 3.61 (2H, w s), 4.27 (2H, k , 9-71 Gu), 12.31 (1H, w s).

Example 148

Preparation of M-(2-(diethylamino)ethyl|-3-ethoxy-M, 6,7-trimethyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoY3,2-s| Ipyridine-2-carboxamide

EC,

M-EI 00-22

M, ke x Me me s OE

Me M (9) re

By a procedure similar to that of Example 146, the title compound (10 mg, 12 95) was obtained as a pale yellow oil from the compound of Example 147 (60 mg, 0.16 mmol) and phenacyl bromide (196 mg, 0.985 mmol ). "H-NMR (300 MHz, SOSIz) 6: 0.80-1.15 (6H, m), 1.34 (ZH, t, 9-71 Hu), 2.21-2.80 (12H, m ), 3.16 (ZH, s), 3.62 (2H, w s), 4.22 (2H, k, 9-71 Hz), 5.67 (2H, s), 7.54 (2H, t, 9-7.5 Hu), 7.66 (1TN, t, U-7.5 Hu), 8.08 (2H, dd, U-8.1, 1.5 Hz).

Example 149

Preparation of M-/1-(hydroxyacetyl)piperidin-4-yl|-3-methoxy-6-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno|3,2- c|Ipyridine-2-carboxamide (9) on u o U

M iz s OMe

Me M (8) ri

By a procedure similar to that of Example 25, the title compound (224 mg, 80 95) was obtained as a white powder from the compound of Auxiliary Example 78 (200 mg, 0.560 mmol), 2-(4-aminopiperidin-1-yl )-2-oxoethanol hydrochloride (142 mg, 0.727 mmol) and triethylamine (101 μL, 0.727 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.38-1.66 (2H, m), 1.79-1.92 (2H, m), 2.26-2.35 (ZH, m), 2.78-2.94 (1Н, m), 3.03-3.18 (1Н, m), 3.58-3.71 (1Н, m), 3.94-4.14 ( 6H, m), 4.18-4.30 (1H, m), 4.51 (1H, t, 9U-5.3 Hz), 5.68 (2H, s), 6.86 (1H, s ), 7.56-7.69 (ЗН, m), 7.71-7.80 (1Н, m), 8.07-8.16 (2Н, m).

Example 150

Preparation of /3-ethoxy-M-|1-(hydroxyacetyl)piperidin-4-yl|-6-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno|Z3,2 -c|Ipyridine-2-carboxamide

(c) he u

M

8-4 and s OB

Me M (o) ri

By a procedure similar to that of Example 25, the title compound (178 mg, 65 95) was obtained as a white powder from the compound of Auxiliary Example 79 (200 mg, 0.538 mmol), 2-(4-aminopiperidin-1-yl )-2-oxoethanol hydrochloride (142 mg, 0.727 mmol) and triethylamine (101 μL, 0.727 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.30 (With H, t, 9U-7.1 Hz), 1.37-1.61 (2 H, m), 1.84-1 .95 (2 N, m), 2.30 (3

N, c), 2.76-2.91 (1 N, m), 3.02-3.18 (1 N, m), 3.59-3.73 (1 N, m), 3.95 -4.13 (With N, m), 4.21-4.33 (With N, m), 4.51 (1 N, t, U-5.4 Hz), 5.68 (2 N, s), 6.86 (1 N, s), 7.57-7.70 (Z H, m), 7.71-7.79 (1 N, m), 8.07-8.17 (2 N, m ).

Example 151

Preparation of 3-methoxy-5-methyl-2-(piperidin-1-ylcarbonyl)thieno|3,2-c|quinolin-4(5H)-one (c) in still ОМе

IM (c)

Me

By a method similar to the method given in Example 1, the title compound was obtained from the compound of Auxiliary Example 84 and piperidine.

РХ/МС 357 (М.Н).

Example 152

Preparation of 2-(2,6-dimethylmorpholin-4-yl)ucarbonyl|-3-methoxy-5-methylthienoic|3,2-c|quinolin-4(5H)-one

Me 8; / (

M|c)

R i zt OMe Me

M (6)

Me

By a method similar to the method given in Example 1, the title compound was obtained from the compound of Auxiliary Example 84 and 2,6-dimethylmorpholine.

РХ/МС 387 (М.Н).

Example 153

Preparation of 2-((4-benzylpiperidin-1-yl)carbonyl|-3-methoxy-5-methylthieno|3,2-siquinolin-4(5H)-one by

M

WITH

And with OMe

M (c);

Me

By a method similar to that given in Example 1, the title compound was obtained from the compound of Auxiliary Example 84 and 4-benzylpiperidine.

РХ/МС 447 (МН).

Example 154

Preparation of /-M-(2-(3,4-dimethoxyphenyl)ethyl|-3-methoxy-M, 5-dimethyl-4-oxo-4,5-dihydrothienoic|3,2- sequinoline-2-carboxamide

Ome

Ωe (in)

M x Me xx OMe

M (c);

Me

By a method similar to the method given in Example 1, the title compound was obtained from the compound of Auxiliary Example 84 and 2-(3,4-dimethoxyphenyl)-M-methylethanamine.

РХ/МС 467 (MN).

Example 155

Preparation of 3-methoxy-M, M-bis(2-methoxyethyl)-5-methyl-4-oxo-4,5-dihydrothieno|3,2-c)quinoline-2-carboxamide

OMe (F) ,-

M

R; t OMe OMe

M (F)

Me

By a method similar to the method given in Example 1, the title compound was obtained from the compound of Auxiliary Example 84 and 2-methoxy-N-(2-methoxyethyl)ethanamine.

РХ/МС 405 (М.Н).

Example 156

Preparation of 3-methoxy-5-methyl-2-(octahydroisoquinolin-2(1H)-ylcarbonyl)thieno|3,2-c|quinolin-4(5H)-one

(in);

m)

Their xx OMe

M (c);

Me

By a method similar to the method given in Example 1, the title compound was obtained from the compound of Auxiliary Example 84 and decahydroisoquinoline.

РХ/МС 411 (М.Н).

Example 157

Preparation of M-ethyl-M-(1-(3-methoxy-5-methyl-4-oxo-4,5-dihydrothieno|3,2-c|quinoline-2-ylcarbonyl|pyrrolidine-3-ilyacetamide)

F (c) with Kh

R M "Me xx OMe Ei

M (c);

Me

By a method similar to that given in Example 1, the title compound was obtained from the compound of Auxiliary Example 84 and M-ethyl-M-pyrrolidin-3-ylacetamide.

РХ/МС 428 (INN).

Example 158

Preparation of /-M-1-((3-methoxy-5-methyl-4-oxo-4,5-dihydrothienoiZ,2-c|quinoline-2-ylcarbonyl|pyrrolidine-

Z-iliacetamide them (in) 1 X

Z X ih Me xx OMe

M (c);

Me

By a method similar to that given in Example 1, the title compound was obtained from the compound of Auxiliary Example 84 and M-pyrrolidin-3-ylacetamide.

РХ/МС 400 (M.N).

Example 159

Preparation of M-cyclohexyl-M-ethyl-3-methoxy-5-methyl-4-oxo-4,5-dihydrothienoi3,2-c|quinoline-2-carboxamide o);

M, x E xx OMe

M (F)

Me

By a method similar to the method given in Example 1, the title compound was obtained from the compound of Auxiliary Example 84 and M-ethylcyclohexanamine.

РХ/МС 399 (М.Н).

Example 160

Preparation of M-(3,3-diphenylpropyl)-3-methoxy-5-methyl-4-oxo-4,5-dihydrothieno|3,2-c|quinoline-2-carboxamide by

M j xx OMe

M (6)

Me

A solution of the compound of Auxiliary Example 84 in DMF (0.10 M, 0.601 mL, 60 μmol) was diluted with DMF (0.200 mL) and a solution of 3,3-diphenylpropan-1-amine in DMF (1.0 M, 0.062 mL, 62 μmol) was added ), and solution

NEW and MU5SO in a 1:11 mixture in DMF (0.50 M, 0.134 ml, 67 μmol). The resulting mixture was shaken at room temperature for 16 hours. Dichloromethane (2 ml) and water (1 ml) were added to the reaction mixture. After stirring for 2.5 hours, sodium bicarbonate (7 mg) was added and the mixture was stirred. The organic layer was filtered through a Teflon filter (registered trademark) to separate the aqueous layer and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (21.9 mg, 76 Vol).

РХ/МС 483 (М.Н).

Example 161

Preparation of 5-butyl-M-cyclopropyl-3-methoxy-4-oxo-4,5-dihydrothieno-3,2-c|quinoline-2-carboxamide

M still xx OMe g

Me

By a method similar to that given in Example 1, the title compound was obtained from the compound of Auxiliary Example 103 and cyclopropanamine.

РХ/МС 371 (М-Н).

Example 162

Preparation of M-benzyl-5-butyl-3-methoxy-4-oxo-4,5-dihydrothieno-3,2-c|quinoline-2-carboxamide

"Dk,

M

R xx OMe

M (c); more

By a method similar to that given in Example 1, the title compound was obtained from the compound of Auxiliary Example 103 and 1-phenylmethanamine.

РХ/МС 421 (М.Н).

Example 163

Preparation of M-(1,3-benzodioxol-5-ylmethyl)-5-butyl-3-methoxy-4-oxo-4,5-dihydrothieno|3,2-c)quinoline-2-carboxamide - o (F)

M

R hu OMe

M (F) ve

By a method similar to the method given in Example 1, the title compound was obtained from the compound of Auxiliary Example 103 and 1-(1,3-benzodioxol-5-yl)methanamine.

РХ/МС 465 (М.Н).

Example 164

Preparation of 5-butyl-3-methoxy-4-oxo-M-(3-phenylpropyl)-4,5-dihydrothieno|3,2-c|quinoline-2-carboxamide p,

She

R xx OMe go

Me

By a method similar to the method given in Example 1, the title compound was obtained from the compound of Auxiliary Example 103 and 3-phenylpropan-1-amine.

РХ/МС 449 (М.Н).

Example 165

Preparation of 5-butyl-3-methoxy-N-(2-methoxyethyl)-4-oxo-4,5-dihydrothieno|3,2-c)quinoline-2-carboxamide

Omg oh,-

M

R xx OMe g

Me

By a method similar to that given in Example 1, the title compound was obtained from the compound of Auxiliary Example 103 and 2-methoxyethanamine.

РХ/МС 389 (М--Н).

Example 166

Preparation of 5-butyl-3-methoxy-4-oxo-M-(tetrahydrofuran-2-ylmethyl)-4,5-dihydrothieno|3,2-s|quinoline-2-carboxamide about 8-7

M (c) same xx OMe go

Me

By a method similar to that given in Example 1, the title compound was obtained from the compound of Auxiliary Example 103 and 1-(tetrahydrofuran-2-yl)methanamine.

РХ/МС 415 (М.Н).

Example 167

Preparation of 5-butyl-M-(1-ethylpropyl)-3-methoxy-4-oxo-4,5-dihydrothieno|3,2-s|quinoline-2-carboxamide

E o 0)A-ye

M

R х ОМе го

Me

By a method similar to that given in Example 1, the title compound was obtained from the compound of Auxiliary Example 103 and pentane-33-amine.

РХ/МС 401 (М--Н).

Example 168

Preparation of 5-butyl-3-methoxy-4-oxo-M-prop-2-yn-1-yl-4,5-dihydrothieno|3,2-c|quinoline-2-carboxamide

ГФ) /у-ь

M

R xx OMe go

Me

By a method similar to the method given in Example 1, the title compound was obtained from the compound of Auxiliary Example 103 and prop-2-yn-1-amine.

РХ/МС 369 (М.Н).

Example 169

Preparation of 5-butyl-M-(2-(3,4-dimethoxyphenyl)ethyl|-3-methoxy-4-oxo-4-5-dihydrothienoic-3,2-syquinoline-2-carboxamide

Ome

OMe (F)

M

R

HU OMe

M (c); more

By a method similar to that given in Example 1, the title compound was obtained from the compound of Auxiliary Example 103 and 2-(3,4-dimethoxyphenyl)ethanamine.

РХ/МС 495 (МН).

Example 170

Preparation of 5-butyl-3-methoxy-M-I|3-(1-methylethoxy)propyl|-4-oxo-4,5-dihydrothieno]3,2-c|quinoline-2-carboxamide

Me )-Me (in); (c) ed

M

R xx OMe g

Me

By a method similar to that given in Example 1, the title compound was obtained from the compound of Auxiliary Example 103 and 3-(1-methylethoxy)propan-1-amine.

РХ/МС 431 (М.Н).

Example 171

Preparation of 5-butyl-N-(furan-2-ylmethyl)-3-methoxy-4-oxo-4,5-dihydrothieno|3,2-s|quinoline-2-carboxamide o Y-

M (c) same with OMe

And MF) 0

By a method similar to that given in Example 1, the title compound was obtained from the compound of Auxiliary Example 103 and 1-furan-2-ylmethanamine.

РХ/МС 411 (МН).

Example 172

Preparation of 5-butyl-33-methoxy-4-oxo-M-(3-(2-oxopyrrolidin-1-yl)propyl|-4,5-dihydrothieno|3,2-syquinoline-2-carboxamide

M

(in); ed

M (c) same xx OMe

I. Shk o)

By a method similar to the method given in Example 1, the title compound was obtained from the compound of Auxiliary Example 103 and 1-(3-aminopropyl)pyrrolidin-2-one.

РХ/МС 456 (М.Н).

Example 173

Preparation of 5-butyl-3-methoxy-2-(piperidin-1-ylcarbonyl)thieno|3,2-c|quinolin-4(5H)-one c)

MIN,

WITH

Ххх ОМе го

Me

By a method similar to that given in Example 1, the title compound was obtained from the compound of Auxiliary Example 103 and piperidine.

РХ/МС 399 (М.Н).

Example 174

Preparation of 5-butyl-2-((2,6-dimethylmorpholin-4-yl)carbonyl|-3-methoxythieno|3,2-c)quinolin-4(5H)-one

Me

M (c);

R ik kt OMe Me

M (F) ve

By a method similar to the method given in Example 1, the title compound was obtained from the compound of Auxiliary Example 103 and 2,6-dimethylmorpholine.

РХ/МС 429 (INN).

Example 175

Preparation of 2-((4-benzylpiperidin-1-yl)carbonyl|-5-butyl-3-methoxythienoi3,2-c|quinolin-4(5H)-one (o);

M

X s OMe go

Me

By a method similar to that given in Example 1, the title compound was obtained from the compound of Auxiliary Example 103 and 4-benzylpiperidine.

РХ/МС 489 (INN).

Example 176

Preparation of 5-butyl-M-(2-(3,4-dimethoxyphenyl)ethyl|-3-methoxy-M-methyl-4-oxo-4,5-dihydrothienoic-3,2-syquinoline-2-carboxamide

Ome

Oh, O

M

5 x Me hu OMe g

Me

By a method similar to that given in Example 1, the title compound was obtained from the compound of Auxiliary Example 103 and 2-(3,4-dimethoxyphenyl)-M-methylethanamine.

РХ/МС 509 (МН).

Example 177

Preparation of 5-butyl-3-methoxy-N,N-bis(2-methoxyethyl)-4-oxo-4,5-dihydrothieno-3,2-c|quinoline-2-carboxamide

OMe (o) ,-

M

R, nt OMe OMe

I. shk c)

AND

By a method similar to the method given in Example 1, the title compound was obtained from the compound of Auxiliary Example 103 and 2-methoxy-N-(2-methoxyethyl)ethanamine.

РХ/МС 447 (М.Н).

Example 178

Preparation of 5-butyl-3-methoxy-2-(octahydroisoquinolin-2(1H)-ylcarbonyl)thieno|3,2-c)quinolin-4(5H)-one (6)

M

WITH

Ххх ОМе го

Me

By a method similar to the method given in Example 1, the title compound was obtained from the compound of Auxiliary Example 103 and decahydroisoquinoline.

РХ/МС 453 (М.Н).

Example 179

Preparation of M-1-(5-butyl-3-methoxy-4-oxo-4,5-dihydrothienoic acid) (c) with Zh

From their M' Me s OMe eyi

I. shk c) ve

By a method similar to the method given in Example 1, the title compound was obtained from the compound of Auxiliary Example 103 and M-ethyl-M-pyrrolidin-3-ylacetamide.

РХ/МС 470 (М--Н).

Example 180

Preparation of M-1-(5-butyl-Z3-methoxy-4-oxo-4,5-dihydrothienoi|Z3,2-c|quinolin-2-yl/ucarbonyl|pyrrolidin-3-yl acetamide their (c)

And in

H N o xx OMe go

Me

By a method similar to that given in Example 1, the title compound was obtained from the compound of Auxiliary Example 103 and M-pyrrolidin-3-ylacetamide.

РХ/МС 442 (М.Н).

Example 181

Preparation of 5-butyl-M-cyclohexyl-M-ethyl-3-methoxy-4-oxo-4,5-dihydrothienoi3,2-c|quinoline-2-carboxamide o;

M

H E s OMe go

Me

By a method similar to the method given in Example 1, the title compound was obtained from the compound of Auxiliary Example 103 and M-ethylcyclohexaneamine.

РХ/МС 441 (М.Н).

Example 182

Preparation of 5-butyl-M-(3,3-diphenylpropyl)-3-methoxy-4-oxo-4,5-dihydrothieno|3,2-c)quinoline-2-carboxamide;

M zh s OMe go

Me

By a method similar to that of Example 160, the title compound was prepared from the compound of Auxiliary Example 103 and 3,3-diphenylpropan-1-amine.

РХ/МС 525 (М.Н).

Example 183

Preparation of M-benzyl-3-methoxy-4-oxo-5-(pyridin-2-ylmethyl)-4,5-dihydrothieno|3,2-c)quinoline-2-carboxamide trifluoroacetate a,

M

R

HU OMe

M (F)

Co

AM SES,

By a method similar to the method given in Example 1, the title compound was obtained from the compound of Auxiliary Example 19 and 1-phenylmethanamine.

РХ/МС 456 (INN).

Example 184

Preparation of trifluoroacetate M-(1,3-benzodioxol-5-ylmethyl)-3-methoxy-4-oxo-5-(pyridin-2-ylmethyl)-4,5-dihydrothienoyl3,2-siquinoline-2-carboxamide - o ( F)

M

R xx OMe

M (F)

Co

DM SeSO, N

By a method similar to the method given in Example 1, the title compound was obtained from the compound of Auxiliary Example 19 and 1-(1,3-benzodioxol-5-ylumethanamine).

РХ/МС 500 (INN).

Example 185

Preparation of 3-methoxy-4-oxo-M-(3-phenylpropyl)-5-(pyridin-2-ylmethyl)-4,5-dihydrothienoic 3,2-syquinoline-2-carboxamide trifluoroacetate;

M

R

HU OMe

M (c);

AM SeSO, N

By a method similar to the method given in Example 1, the title compound was obtained from the compound of Auxiliary Example 19 and 3-phenylpropan-1-amine.

РХ/МС 484 (М.Н).

Example 186

Preparation of 3-methoxy-M-(2-methoxyethyl)-4-oxo-5-(pyridin-2-ylmethyl)-4,5-dihydrothieno|3,2-syquinoline-2-carboxamide trifluoroacetate

Omg oh,-

M j xx OMe

I. Shk o)

So dm SE.SO,N

By a method similar to the method given in Example 1, the title compound was obtained from the compound of Auxiliary Example 19 and 2-methoxyethanamine.

РХ/МС 424 (М.Н).

Example 187

Preparation of 3-methoxy-4-oxo-5-(pyridin-2-ylmethyl)-M-(tetrahydrofuran-2-ylmethyl)-4,5-dihydrothienoyl3,2-siquinoline-2-carboxamide trifluoroacetate 8-7

M (in)

And xx OMe

I MF) xx

M and SE.SO,N

By a method similar to the method given in Example 1, the title compound was obtained from the compound of Auxiliary Example 19 and 1-(tetrahydrofuran-2-yl)methanamine.

РХ/МС 450 (М--Н).

Example 188

Preparation of M-(1-ethylpropyl)-3-methoxy-4-oxo-5-(pyridin-2-ylmethyl)-4,5-dihydrothieno|3,2-c|quinoline-2-carboxamide trifluoroacetate

E o 0)A-eE

M still hu OMe

I MF)

Co

DM SEZSO, N

By a method similar to that given in Example 1, the title compound was obtained from the compound of Auxiliary Example 19 and pentane-3-amine.

РХ/МС 436 (М.Н).

Example 189

Preparation of M-cyclohexyl-3-methoxy-4-oxo-5-(pyridin-2-ylmethyl)-4,5-dihydrothieno|3,2-c)quinoline-2-carboxamide trifluoroacetate o);

M

And xx OMe

I MF) xx. m

SE.SO,N

By a method similar to that given in Example 1, the title compound was obtained from the compound of Auxiliary Example 19 and cyclohexanamine.

РХ/МС 448 (М.Н).

Example 190

Preparation of trifluoroacetate 3-methoxy-4-oxo-N-prop-2-yn-1-yl-5-(pyridin-2-ylmethyl)-4,5-dihydrothieno|3,2-c)quinoline-2-carboxamide

Go) /-ЩЩ

M

R xx OMe

I. M is) xx

M

27 SE.SO,N

By a method similar to that given in Example 1, the title compound was obtained from the compound of Auxiliary Example 19 and prop-2-yn-1-amine.

РХ/МС 404 (М.Н).

Example 191

Preparation of M-(2-(3,4-dimethoxyphenyl)ethyl|-3-methoxy-4-oxo-5-(pyridin-2-ylmethyl)-4,5-dihydrothienoyl-3,2-siquinoline-2-carboxamide trifluoroacetate

Ome

OMe 6)

M

And xx OMe

I. shk c)

XX

M and SE.SO,N

By a method similar to that given in Example 1, the title compound was obtained from the compound of Auxiliary Example 19 and 2-(3,4-dimethoxyphenyl)ethanamine.

РХ/МС 530 (М--Н).

Example 192

Preparation of trifluoroacetate trifluoroacetate

Me )-Me (c) o ed

M

R xx OMe

I. ShK is)

Court dm SE.SO,N

By a method similar to the method given in Example 1, the title compound was obtained from the compound of Auxiliary Example 19 and 3-(1-methylethoxy)propan-1-amine.

РХ/МС 466 (М.Н).

Example 193

Preparation of trifluoroacetate trifluoroacetate

MN o)

M (6) 5th xx OMe

I. M is) and

M and SE.SO,N

By a method similar to the method given in Example 1, the title compound was obtained from the compound of Auxiliary Example 19 and 3-aminoazepan-2-one.

РХ/МС 477 (М.Н).

Example 194

Preparation of 3-methoxy-4-oxo-M-|3-(2-oxopyrrolidin-1-yl)propyl|-5-(pyridin-2-ylmethyl)-4,5-dihydrothienoyl-3,2-siquinoline-2-carboxamide trifluoroacetate

M

(F) ed them (c)

A sh OMe

I. shk c) xx

M and SE.SO,N

By a method similar to that given in Example 1, the title compound was obtained from the compound of Auxiliary Example 159 and 1-(3-aminopropyl)pyrrolidin-2-one.

РХ/МС 491 (М--Н).

Example 195

Preparation of 3-methoxy-2-(piperidin-1-ylcarbonyl)-5-(pyridin-2-ylmethyl)thieno|Y3,2-c|quinolin-4(5H)-one trifluoroacetate 6) and

WITH

X with OMe

I MF) xx

M

- SEZSO, N

By a method similar to that given in Example 1, the title compound was obtained from the compound of Auxiliary Example 19 and piperidine.

РХ/МС 434 (М.Н).

Example 196

Preparation of trifluoroacetate 2-(2,6-dimethylmorpholin-4-yl)carbonyl|-3-methoxy-5-(pyridin-2-ylmethyl)thionoi|3,2-syquinolin-4(5H)-one

Me o); / (

M (in)

H i ki tOME Me shk is) xx

M

- SE.SO,N

By a method similar to the method given in Example 1, the title compound was obtained from the compound of Auxiliary Example 19 and 2,6-dimethylmorpholine.

РХ/МС 464 (М.Н).

Example 197

Preparation of 2-(4-benzylpiperidin-1-yl)ucarbonyl|-3-methoxy-5-(pyridin-2-ylmethyl)thieno-3,2-syquinolin-4(5H)-one trifluoroacetate c)

M

WITH

X and OMe

And MF) oh

M

- Se.SO,N

By a method similar to that given in Example 1, the title compound was obtained from the compound of Auxiliary Example 19 and 4-benzylpiperidine.

РХ/МС 524 (М.Н).

Example 198

Preparation of //- M-(2-(3,4-dimethoxyphenyl)ethyl|-3-methoxy-M-methyl-4-oxo-5-(pyridin-2-ylmethyl)-4,5-dihydrothienoi3,2-siquinoline -2-carboxamide trifluoroacetate

Ome

Ohm c)

M x Me xx OMe

I MF)

Co

YAM SES,

By a method similar to the method given in Example 1, the title compound was obtained from the compound of Auxiliary Example 19 and 2-(3,4-dimethoxyphenyl)-M-methylethanamine.

РХ/МС 544 (М.Н).

Example 199

Preparation of 3-methoxy-M, M-bis(2-methoxyethyl)-4-oxo-5-(pyridin-2-ylmethyl)-4,5-dihydrothieno|3,2-syquinoline-2-carboxamide trifluoroacetate

Omg oh,-

M more, t OMe OMe

And M is);

Co

DM SESO, N

By a method similar to the method given in Example 1, the title compound was obtained from the compound of Auxiliary Example 19 and 2-methoxy-N-(2-methoxyethyl)ethanamine.

РХ/МС 482 (М.Н).

Example 200

Preparation of trifluoroacetate trifluoroacetate

M

WITH

X xx OMe

I. Shk o)

Su

AM SE.SO,N

By a method similar to that given in Example 1, the title compound was obtained from the compound of Auxiliary Example 19 and decahydroisoquinoline.

РХ/МС 488 (М.Н).

Example 201

Preparation of M-ethyl-M-(1-Z-methoxy-4-oxo-5-(pyridin-2-ylmethyl)-4,5-dihydrothienoi|Z,2-c|quinoline-2-ylcarbonyl)pyrrolidin- 3-illuacetamide trifluoroacetate

F (6) kh

HORROR m me xx OMe Eyi and Mk o)

Co

RA SE.SO,N

By a method similar to that given in Example 1, the title compound was obtained from the compound of Auxiliary Example 19 and M-ethyl-M-pyrrolidin-3-ylacetamide.

РХ/МС 505 (М.Н).

Example 202

Preparation of M-(1-TZ-methoxy-4-oxo-5-(pyridin-2-ylmethyl)-4,5-dihydrothieno|3,2-c|quinolin-2-ylcarbonyl)pyrrolidin-3-ylluacetamide trifluoroacetate

F (6) хи 5-5 M me сх ОМе i. shk o)

Co

RA SE.SO,N

By a method similar to that given in Example 1, the title compound was obtained from the compound of Auxiliary Example 19 and M-pyrrolidin-3-ylacetamide.

РХ/МС 477 (М.Н).

Example 203

Preparation of M-cyclohexyl-M-ethyl-3-methoxy-4-oxo-5-(pyridin-2-ylmethyl)-4,5-dihydrothienoi|3,2-syquinoline-2-carboxamide trifluoroacetate shk,

M, x Kk

Yes Ome

I. M is) co

M Seg.SO,N

By a method similar to the method given in Example 1, the title compound was obtained from the compound of Auxiliary Example 19 and M-ethylcyclohexanamine.

РХ/МС 476 (М.Н).

Example 204

Preparation of M-(3,3-diphenylpropyl)-33-methoxy-4-oxo-5-(pyridin-2-ylmethyl)-4,5-dihydrothienoic acid trifluoroacetate 3,2-syquinoline-2-carboxamide;

M j xx OMe

And M is) xx

AM SeSO, N

By a method similar to that given in Example 160, the title compound was obtained from the compound of Auxiliary Example 19 and 3,3-diphenylpropan-1-amine.

РХ/МС 560 (М--Н).

Example 205

Preparation of M-benzyl-3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno|3,2-c|quinoline-2-carboxamide a,

M j xx OMe

I. Shk o) r:

By a method similar to the method given in Example 1, the title compound was obtained from the compound of Auxiliary Example 7 and 1-phenylmethanamine.

РХ/МС 483 (М.Н).

Example 206

Preparation of M-(1,3-benzodioxol-5-ylmethyl)-3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoyl-3,2-syquinoline-2-carboxamide

What about them xx OMe

I. Shk o) r:

By a method similar to the method given in Example 1, the title compound was obtained from the compound of Auxiliary Example 7 and 1-(1,3-benzodioxol-5-yl)umethanamine.

РХ/МС 527 (М.Н).

Example 207

Preparation of 3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-M-(3-phenylpropyl)-4,5-dihydrothienoic acid, 3,2-syquinoline-2-carboxamide,

M z s OMe

And MF) ih

By a method similar to the method given in Example 1, the title compound was obtained from the compound of Auxiliary Example 7 and 3-phenylpropan-1-amine.

РХ/МС 511 (М--Н).

Example 208

Preparation of 3-methoxy-M-(2-methoxyethyl)-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno|3,2- syquinoline-2-carboxamide

OMe (F) -i-

M

R xx OMe

And Shk is)

H

By a method similar to the method given in Example 1, the title compound was obtained from the compound of Auxiliary Example 7 and 2-methoxyethanamine.

РХ/МС 451 (М--Н).

Example 209

Preparation of M-(1-ethylpropyl)-3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoic-3,2-syquinoline-2-carboxamide

E o 00)A-E

M j xx OMe

I MF) r:

By a method similar to the method given in Example 1, the title compound was obtained from the compound of Auxiliary Example 7 and pentan-3-amine.

РХ/МС 463 (М--Н).

Example 210

Preparation of M-cyclohexyl-3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoic 3,2-c|quinoline-2-carboxamide o);

M still xx OMe

I MF) x

By a method similar to that given in Example 1, the title compound was obtained from the compound of Auxiliary Example 7 and cyclohexanamine.

РХ/МС 475 (М.Н).

Example 211

Preparation of 3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-M-prop-2-yn-1-yl-4,5-dihydrothieno-3,2-c|quinoline-2-carboxamide

GF) ul--

M

I'm sorry

And Shk is)

WITH

By a method similar to the method given in Example 1, the title compound was obtained from the compound of Auxiliary Example 7 and prop-2-yn-1-amine.

РХ/МС 431 (М--Н).

Example 212

Preparation of 3-methoxy-IM-(3-(1-methylethoxy)propyl|-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoic acid and 3,2-syquinoline-2-carboxamide

Me )-Me (c) o ed

M j xx OMe

I. shk c) ih

By a method similar to the method given in Example 1, the title compound was obtained from the compound of Auxiliary Example 7 and 3-(1-methylethoxy)propan-1-amine.

РХ/МС 493 (М.Н).

Example 213

Preparation of 3-methoxy-4-oxo-N-(2-oxoazepan-3-yl)-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno|3,2- syquinoline-2-carboxamide

MN c)

M (F) 5-4 and with OMe

I. shk c) r:

By a method similar to that given in Example 1, the title compound was obtained from the compound of Auxiliary Example 7 and 3-aminoazepan-2-one.

РХ/МС 504 (М.Н).

Example 214

Preparation of M-(furan-2-ylmethyl)-3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoic|3,2- syquinoline-2-carboxamide by

M (in)

X shh Ome

I. shk c)

By a method similar to the method given in Example 1, the title compound was obtained from the compound of Auxiliary Example 7 and 1-furan-2-ylmethanamine.

РХ/МС 473 (МН).

Example 215

Preparation of 3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-N-(3-(2-oxopyrrolidin-1-yl)propyl)-4,5-dihydrothienoyl-3,2-syquinolin-2 -carboxamide

M

(o) ed

M c)

With the same OMe

I MF) x

By a method similar to that given in Example 1, the title compound was obtained from the compound of Auxiliary Example 7 and 1-(3-aminopropyl)pyrrolidin-2-one.

РХ/МС 518 (М--Н).

Example 216

Preparation of 2-(2,6-dimethylmorpholin-4-yl)ucarbonyl|-3-methoxy-5-(2-oxo-2-phenylethyl)thieno|3,2-c)quinolin-4(5H)-one

Me o /h

M c)

R i kt OMe Me

I. M c) x

By a method similar to the method given in Example 1, the title compound was obtained from the compound of Auxiliary Example 7 and 2,6-dimethylmorpholine.

РХ/МС 491 (М--Н).

Example 217

Preparation of 2-(4-benzylpiperidin-1-yl)ucarbonyl|-3-methoxy-5-(2-oxo-2-phenylethyl)uthienoi|3,2-c)quinolin-4(5H)-one c)

M

WITH

X with OMe

there is a SHK)

WITH

By a method similar to the method given in Example 1, the title compound was obtained from the compound of Auxiliary Example 7 and 4-benzylpiperidine.

РХ/МС 551 (М--Н).

Example 218

Preparation of M-(2-(3,4-dimethoxyphenyl)ethyl|-3-methoxy-M-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoiZ,2-c) quinoline-2-carboxamide

Ome

Ohm c)

M x Me with OMe

ShK is) x

By a method similar to the method given in Example 1, the title compound was obtained from the compound of Auxiliary Example 7 and 2-(3,4-dimethoxyphenyl)-M-methylethanamine.

РХ/МС 571 (М--Н).

Example 219

Preparation of 3-methoxy-M, M-bis(2-methoxyethyl)-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno|3,2- sequinoline-2-carboxamide

OMe (in) ,No-

M

R, хи ОМе ОМe

I. M o) h

By a method similar to the method given in Example 1, the title compound was obtained from the compound of Auxiliary Example 7 and 2-methoxy-N-(2-methoxyethyl)ethanamine.

РХ/МС 509 (М.Н).

Example 220

Preparation of 2-(3,4-dihydroisoquinolin-2(1H)-ylcarbonyl)-3-methoxy-5-(2-oxo-2-phenylethyl)uthieno|3,2-c)quinolin-4(5H)-one in )

M

WITH

X xx OMe

I MF)

By a method similar to the method given in Example 1, the title compound was obtained from the compound of Auxiliary Example 7 and 1,2,3,4-tetrahydroisoquinoline.

РХ/МС 509 (М.Н).

Example 221

Preparation of 3-methoxy-2-(octahydroisoquinolin-2(1H)-ylcarbonyl)-5-(2-oxo-2-phenylethyl)thienoyl3,2-c)quinolin-4(5H)-one c)

M

WITH

H

HU OMe

I MF) x

By a method similar to the method given in Example 1, the title compound was obtained from the compound of Auxiliary Example 7 and decahydroisoquinoline.

РХ/МС 515 (М.Н).

Example 222

Preparation of M-(1-73-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoyl3,2-c|quinolin-2-yl)carbonyl)pyrrolidin-3-yl) yauacetamide o (6) c c me u H c OMe

Mo r:

By a method similar to the method given in Example 1, the title compound was obtained from the compound of Auxiliary Example 7 and M-pyrrolidin-3-ylacetamide.

РХ/МС 504 (М.Н).

Example 223

Preparation of M-cyclohexyl-M-ethyl-3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoi|3,2-syquinoline-2-carboxamide o);

M x E

HU OMe

M (c)

WITH

By a method similar to the method given in Example 1, the title compound was obtained from the compound of Auxiliary Example 7 and M-ethylcyclohexanamine.

РХ/МС 503 (М--Н).

Example 224

Preparation of IM-(3,3-diphenylpropyl)-3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoic|3,2-syquinoline-2-carboxamide;

Yes, yes, OMe

M''o r

By a method similar to that given in Example 160, the title compound was obtained from the compound of Auxiliary Example 7 and 3,3-diphenylpropan-1-amine.

РХ/МС 587 (М.Н).

Example 225

Preparation of trifluoroacetate M-(2-(dimethylamino)ethyl|-3-methoxy-5-methyl-4-oxo-4,5-dihydrothienoi|3,2-c)quinoline-2-carboxamide

Me,

M-Me (F) ,- i

R xx OMe

M (c);

Me SSO, N

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 84 and M,M-dimethylethane-1 2-diamine.

РХ/МС 360 (MNN).

Example 226

Preparation of trifluoroacetate 3-methoxy-5-methyl-4-oxo-N-(pyridin-2-ylmethyl)-4,5-dihydrothieno|3,2-c)quinoline-2-carboxamide

He

R that OMe

Min)

Me SE.SO,N

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 84 and 1-pyridin-2-ylmethanamine.

РХ/МС 380 (INN).

Example 227

Preparation of trifluoroacetate 3-methoxy-5-methyl-4-oxo-N-(pyridin-4-ylmethyl)-4,5-dihydrothieno|3,2-c)quinoline-2-carboxamide /

She

R hu OMe

M F)

Me SE.SO,N

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 84 and 1-pyridin-4-ylmethanamine.

РХ/МС 380 (INN).

Example 228

Preparation of 3-methoxy-5-methyl-4-oxo-M-(2-pyrrolidin-1-ylethyl)-4,5-dihydrothienoic acid trifluoroacetate trifluoroacetate

R xx OMe

Min,

Me SR.SO,N

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 84 and 2-pyrrolidin-1-ylethanamine.

РХ/МС 386 (INN).

Example 229

Preparation of trifluoroacetate 3-methoxy-5-methyl-4-oxo-M-(2-pyridin-3-ylethyl)-4,5-dihydrothieno|3,2-c|quinoline-2-carboxamide (6)

M

HU OMe

M (c)

AND

Me SE.SO,N

By a method similar to the method given in Example 5, the title compound was obtained from the compound of Auxiliary Example 84 and 2-pyridin-3-ylethanamine.

РХ/МС 394 (МН).

Example 230

Preparation of C3-methoxy-5-methyl-M-|(5-methylpyrazin-2-ylmethyl|-4-oxo-4,5-dihydrothienoic|C3,2-c|quinoline-2-carboxamide trifluoroacetate -M and M

R z OMe

M c)

Me SEZSO, N

By a method similar to the method given in Example 5, the title compound was obtained from the compound of Auxiliary Example 84 and 1-(5-methylpyrazin-2-yl)umethanamine.

РХ/МС 395 (МН).

Example 231

Obtaining | M-I3-(1H-imidazol-1-yl)/propyl|-3-methoxy-5-methyl-4-oxo-4,5-dihydrothienoic|3,2-c|quinoline-2-carboxamide trifluoroacetate -xd

MO about ed. KhM

M

R xx OMe

M o

Me SEZSO, N

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 84 and 3-(1H-imidazol-1-yl)upropan-1-amine.

РХ/МС 397 (MN).

Example 232

Preparation of 3-methoxy-5-methyl-N-(2-(1-methylpyrrolidin-2-yl)ethyl|-4-oxo-4,5-dihydrothienoic|3,2-syquinoline-2-carboxamide trifluoroacetate

M. about Me

She

I xx OMe

M (c);

Me SSO,

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 84 and 2-(1-methylpyrrolidin-2-yl)ethanamine.

РХ/МС 400 (M.N).

Example 233

Preparation of 3-methoxy-5-methyl-4-oxo-N-(2-piperidin-1-ylethyl)-4,5-dihydrothienoic 3,2-c|quinoline-2-carboxamide trifluoroacetate o, (c) ,-

M

R hu OMe

M (in,

Me SR.SO,N

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 84 and 2-piperidin-1-ylethanamine.

РХ/МС 400 (M.N).

Example 234

Preparation of trifluoroacetate M-3-(diethylamino)propyl|-3-methoxy-5-methyl-4-oxo-4,5-dihydrothieno|3,2-c|quinoline-2-carboxamide

EE

M

(c) re D E her still hu OMe

M (c);

Me SEZSO, N

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 84 and M,M-diethylpropane-1,3-diamine.

РХ/МС 402 (М.Н).

Example 235

Preparation of // 3-methoxy-5-methyl-M-(3-morpholin-4-ylpropyl)-4-oxo-4,5-dihydrothienoic|3,2-c|quinoline-2-carboxamide trifluoroacetate

M I) o /- x/

M j xx OMe

M (6)

Me SEZSO, N

By a method similar to the method given in Example 5, the title compound was obtained from the compound of Auxiliary Example 84 and 3-morpholin-4-ylpropan-1-amine.

РХ/МС 416 (М.Н).

Example 236

Preparation of 3-methoxy-5-methyl-N-(3-(4-methylpiperazin-1-yl)propyl|-4-oxo-4,5-dihydrothienoic|3,2-syquinoline-2-carboxamide ditrifluoroacetate

M M-Me o /8-

M

X xx OMe

M (c)

Me 2 SSO

By a procedure similar to that of Example 5, the title compound was prepared from the compound of Auxiliary Example 84 and 3-(4-methylpiperazin-1-yl)/propan-1-amine.

РХ/МС 429 (М.Н).

Example 237

Preparation of trifluoroacetate M-(4-(diethylamino)-1-methylbutyl|-33-methoxy-5-methyl-4-oxo-4,5-dihydrothieno|3,2-syquinoline-2-carboxamide

IS

M-EI

Me (o)

M x xx OMe

M (c);

Me SE.SO,N

By a method similar to the method given in Example 5, the title compound was obtained from the compound of Auxiliary Example 84 and M',M'-diethylpentane-1 4-diamine.

РХ/МС 430 (INN).

Example 238

Preparation of M-(1-benzylpyrrolidin-3-yl)-3-methoxy-5-methyl-4-oxo-4,5-dihydrothienoyl3,2-c|quinoline-2-carboxamide trifluoroacetate

M

(in);

She

R

HU OMe

M (c);

Me SE.SO,N

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 84 and 1-benzylpyrrolidin-3-amine.

РХ/МС 448 (М.Н).

Example 239

Preparation of M-(1-benzylpiperidin-4-yl)-3-methoxy-5-methyl-4-oxo-4,5-dihydrothieno|3,2-c|quinoline-2-carboxamide trifluoroacetate

M i sh,

M

R z OMe

M (c);

Me SESO, N

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 84 and 1-benzylpiperidine-4-amine.

РХ/МС 462 (МН).

Example 240

Preparation of 3-methoxy-M, 5-dimethyl-M-(1-methylpyrrolidin-3-yl)-4-oxo-4,5-dihydrothienoi3,2-c|quinoline-2-carboxamide trifluoroacetate m Me

M, x Me xx OMe

M (6)

Me SeZSO, N

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 84 and M, 1-dimethylpyrrolidine-3-amine.

РХ/МС 386 (MN).

Example 241

Preparation of 3-methoxy-5-methyl-2-|((4-methyl-1,4-diazepan-1-yl)ucarbonyligieno|3,2-c|quinolin-4(5H)-one trifluoroacetate

Co

WITH

H

M (in)

Me SEZSO, N

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 84 and 1-methyl-1,4-diazepane.

РХ/МС 386 (MN).

Example 242

Preparation of trifluoroacetate 2-(4-ethylpiperazin-1-yl/ucarbonyl|-3-methoxy-5-methylthienoyl3,2-c|quinolin-4(5H)-one

Oh /t

M M-EI e ku

X with OMe

M (c)

Me SE.SO,N

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 84 and 1-ethylpiperazine.

РХ/МС 386 (MN).

Example 243

Preparation of M-(2-(diethylamino)ethyl|-3-methoxy-M, 5-dimethyl-4-oxo-4,5-dihydrothienoic|3,2-c|quinoline-2-carboxamide trifluoroacetate

EC

M-E (F) No-

M x Me xx OMe

M (in)

Me SeZSO, N

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 84 and M,M-diethyl-M'-methylethane-1,2-diamine.

РХ/МС 402 (М.Н).

Example 244

Preparation of trifluoroacetate

V, i o) i

M

WITH

X with OMe them (6)

Me SeZSO, N

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 84 and 1-(25)-pyrrolidin-2-ylmethyl|pyrrolidine.

РХ/МС 426 (М.Н).

Example 245

Preparation of 3-methoxy-5-methyl-2-((4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl|hyeno-3,2-c|quinolin-4(5H)-one trifluoroacetate c) where

Z x s OMe

M (c)

Me SEZSO, N

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 84 and 4-pyrrolidin-1-ylpiperidine.

РХ/МС 426 (М.Н).

Example 246

Preparation of 3-methoxy-5-methyl-2-((4-phenylpiperazin-1-yl)carbonylhieno|3,2-s|quinolin-A(5H)-one trifluoroacetate bi oo z xx OMe

M (6)

Me SE.SO,N

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 84 and 1-phenylpiperazine.

РХ/МС 434 (М.Н).

Example 247

Preparation of M-(2-cyanoethyl)-33-methoxy-5-methyl-4-oxo-M-(pyridin-333-ylmethyl)-4,5-dihydrothienoic trifluoroacetate 3,2-syquinoline-2-carboxamide

SM

8; ;

M -M 2 -/ s OMe

M (in)

Me SEZSO, N

By a method similar to that of Example 5, the title compound was prepared from the compound of Auxiliary Example 84 and 3-pyridin-3-ylmethyl)amino|ipropanenitrile.

РХ/МС 433 (М.Н).

Example 248

Preparation of trifluoroacetate 2-1C4-(1,3-benzodioxol-5-ylmethyl)piperazin-1-ylcarbonyl)-3-methoxy-5-methylthieno|3,2-syquinolin-4(5H)-one

That in)

oh

M M more xx OMe

M (in)

Me Se.SO,N

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 84 and 1-(1,3-benzodioxol-5-ylmethyl)piperazine.

РХ/МС 492 (М.Н).

Example 249

Preparation of trifluoroacetate 5-butyl-N-(2-(dimethylamino)ethyl|-3-methoxy-4-oxo-4,5-dihydrothienoi3,2-c|quinoline-2-carboxamide

Me,

M-Me (F) ,-

M

R s OMe mo / Se.SO,N

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 103 and M,M-dimethylethane-1 2-diamine.

РХ/МС 402 (МН).

Example 250

Preparation of trifluoroacetate 5-butyl-3-methoxy-4-oxo-N-(pyridin-2-ylmethyl)-4,5-dihydrothienoyl3,2-c|quinoline-2-carboxamide in

Bl

R hu OMe

M (c); / SEZSO, N

By a method similar to the method given in Example 5, the title compound was obtained from the compound of Auxiliary Example 103 and 1-pyridin-2-ylmethanamine.

РХ/МС 422 (МН).

Example 251

Preparation of 5-butyl-3-methoxy-4-oxo-N-(pyridin-4-ylmethyl)-4,5-dihydrothienoyl-3,2-c|quinoline-2-carboxamide of trifluoroacetate; and M

R xx OMe

M (c); in SE, SO, N

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 103 and 1-pyridin-4-ylmethanamine.

РХ/МС 422 (МН).

Example 252

Preparation of trifluoroacetate 5-butyl-3-methoxy-4-oxo-N-(2-pyrrolidin-1-ylethyl)-4,5-dihydrothieno-3,2-c|quinoline-2-carboxamide

(about) ,-

M z xx OMe g,

Me Se.SO,N

By a method similar to the method given in Example 5, the title compound was obtained from the compound of Auxiliary Example 103 and 2-pyrrolidin-1-ylethanamine.

РХ/МС 428 (М.Н).

Example 253

Preparation of 5-butyl-33-methoxy-4-oxo-M-(2-pyridin-3-ylethyl)-4,5-dihydrothieno|3,2-c|quinoline-2-carboxamide of trifluoroacetate ih / M 6)

M is still OMe

I. Shk o) / SEZSO, N

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 103 and 2-pyridin-3-ylethanamine.

РХ/МС 436 (М.Н).

Example 254

Preparation of trifluoroacetate 5-butyl-3-methoxy-M-(5-methylpyrazin-2-ylmethyl)|-4-oxo-4,5-dihydrothieno|3,2-c)quinoline-2-carboxamide -M (F) "Zh

R with OMe

there is a SHK)

In SEZSO, N

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 103 and 1-(5-methylpyrazin-2-yl)umethanamine.

РХ/МС 437 (М.Н).

Example 255

Preparation of 5-butyl-N-I(3-(1H-imidazol-1-yl)propyl|-3-methoxy-4-oxo-4,5-dihydrothieno-3,2-c|quinoline-2-carboxamide trifluoroacetate

M o pe d hmm

M j xx OMe

I. MF) / SEZSO, N

By a method similar to the method given in Example 5, the title compound was obtained from the compound of Auxiliary Example 103 and 3-(1H-imidazol-1-yl)upropan-1-amine.

РХ/МС 439 (М.Н).

Example 256

Preparation of trifluoroacetate 5-butyl-3-methoxy-N-(2-(1-methylpyrrolidin-2-yl)ethyl|-4-oxo-4,5-dihydrothienoyl3,2-syquinoline-2-carboxamide

M, oh Me

M j xx OMe

And, Mk 6) you SSO,

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 103 and 2-(1-methylpyrrolidin-2-yl)ethanamine.

РХ/МС 442 (М.Н).

Example 257

Preparation of trifluoroacetate 5-butyl-3-methoxy-4-oxo-N-(2-piperidin-1-ylethyl)-4,5-dihydrothieno|3,2-c)quinoline-2-carboxamide

/B, o H-

M

With ОМе

I. Shk o) / Seg.SO,N

By a method similar to the method given in Example 5, the title compound was obtained from the compound of Auxiliary Example 103 and 2-piperidin-1-ylethanamine.

РХ/МС 442 (М.Н).

Example 258

Preparation of trifluoroacetate 5-butyl-M-3-(diethylamino)propyl|-3-methoxy-4-oxo-4,5-dihydrothienoic|3,2-s|quinoline-2-carboxamide

IS

M

(o) ed

M

R with OMe

I. M c) / SeSO, N

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 103 and M,M-diethylpropane-1,3-diamine.

РХ/МС 444 (М.Н).

Example 259

Preparation of trifluoroacetate 5-butyl-3-methoxy-N-(3-morpholin-4-ylpropyl)-4-oxo-4,5-dihydrothienoi3,2-c|quinoline-2-carboxamide

M Iv) o /-/ x/

M

X with OMe

I MF) / SeSO,N

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 103 and 3-morpholin-4-ylpropan-1-amine.

РХ/МС 458 (М.Н).

Example 260

Preparation of 5-butyl-3-methoxy-N-I3-(4-methylpiperazin-1-yl)propyl|-4-oxo-4-5-dihydrothienoi3,2-syquinoline-2-carboxamide ditrifluoroacetate

M M-Me o /8-

M

AND

Yes Ome

I. shk c)

Me g 2 SEZSO,N

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 103 and 3-(4-methylpiperazin-1-yl)propan-1-amine.

РХ/МС 471 (М.Н).

Example 261

Preparation of trifluoroacetate 5-butyl-M-(4-(diethylamino)-1-methylbutyl|-3-methoxy-4-oxo-4,5-dihydrothieno|3,2-syquinoline-2-carboxamide

EC

M-EI

Me 6)

M still with OMe

I. Shk o)

In SE, SO, N

By a method similar to the method given in Example 5, the title compound was obtained from the compound of Auxiliary Example 103 and M',M'-diethylpentane-1 4-diamine.

РХ/МС 472 (М.Н).

Example 262

Preparation of trifluoroacetate M-(1-benzylpyrrolidin-3-yl)-5-butyl-3-methoxy-4-oxo-4,5-dihydrothieno|3,2-c|quinoline-2-carboxamide

M

(6)

M still xx OMe

And M is

In SEASON

By a method similar to the method given in Example 5, the title compound was obtained from the compound of Auxiliary Example 103 and 1-benzylpyrrolidin-3-amine.

РХ/МС 490 (INN).

Example 263

Preparation of M-(1-benzylpiperidin-4-yl)-5-butyl-3-methoxy-4-oxo-4,5-dihydrothieno|3,2-c|quinoline-2-carboxamide trifluoroacetate

M,

WHAT,

M

R xx OMe

M (c); / SeSO, N

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 103 and 1-benzylpiperidine-4-amine.

РХ/МС 504 (М.Н).

Example 264

Preparation of 5-butyl-3-methoxy-M-methyl-M-(1-methylpyrrolidin-3-yl)-4-oxo-4,5-dihydrothienoi|3,2-syquinoline-2-carboxamide trifluoroacetate m7Me (c);

M x Me xx OMe

M (c); / SSO,

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 103 and M, 1-dimethylpyrrolidine-3-amine.

РХ/МС 428 (INN).

Example 265

Preparation of 5-butyl-3-methoxy-2-|((4-methyl-1,4-diazepan-1-yl)ucarbonyligieno|3,2-c|quinolin-4(5H)-one trifluoroacetate

GF) tuMe and

WITH

X with OMe

I. M); / SE.SO,N

By a method similar to the method given in Example 5, the title compound was obtained from the compound of Auxiliary Example 103 and 1-methyl-1,4-diazepane.

РХ/МС 428 (М.Н).

Example 266

Preparation of 5-butyl-2-((4-ethylpiperazin-1-yl)ucarbonyl|-3-methoxythieno|3,2-c)quinolin-4(5H)-one trifluoroacetate b/t

M M-E huh

X with OMe

I M) / SEZSO, N

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 103 and 1-ethylpiperazine.

РХ/МС 428 (М.Н).

Example 267

Preparation of trifluoroacetate 5-butyl-M-(2-(diethylamino)ethyl|-3-methoxy-M-methyl-4-oxo-4,5-dihydrothienoi3,2-syquinoline-2-carboxamide

EC

M-EI (c); ,i-

M

5 x Me with OMe

Mo / SeSO,N

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 103 and M,M-diethyl-M'-methylethane-1,2-diamine.

РХ/МС 444 (М.Н).

Example 268

Preparation of trifluoroacetate 5-butyl-3-methoxy-2-C(25)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-ylcarbonylilugenyl3,2-syquinolin-4(5H)-one

V, i o) i

M

WITH

Their with OMe

I MF) / SE.SO,N

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 103 and 1-(25)-pyrrolidin-2-ylmethyl|pyrrolidine.

РХ/МС 468 (М--Н).

Example 269

Preparation of 5-butyl-3-methoxy-2-((4-pyrrolidin-1-ylpiperidin-1-yl)carbonyligieno|3,2-c|quinolin-4(5H)-one trifluoroacetate c) where

WITH

X with OMe

I MF)

In SE, SO, N

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 103 and 4-pyrrolidin-1-ylpiperidine.

РХ/МС 468 (М--Н).

Example 270

Preparation of 5-butyl-3-methoxy-2-((4-phenylpiperazin-1-yl)ucarbonyligieno|3,2-c)quinolin-4(5H)-one trifluoroacetate bi

M M j xx OMe

I, M 6) / SE.SO,N

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 103 and 1-phenylpiperazine.

РХ/МС 476 (М.Н).

Example 271

Preparation of trifluoroacetate /5-butyl-N-(2-cyanoethyl)-3-methoxy-4-oxo-N-(pyridin-3-ylmethyl)-4,5-dihydrothienoic|3,2-syquinoline-2-carboxamide

CM o); ;

M - M

R -/ s OMe

I MF) / SeSO,N

By a method similar to that of Example 5, the title compound was prepared from the compound of Auxiliary Example 103 and 3-(pyridin-3-ylmethyl)amino|propanenitrile.

РХ/МС 475 (М.Н).

Example 272

Preparation of 2-(C4-(1,3-benzodioxol-5-ylmethyl)piperazin-1-ylcarbonyl)-5-butyl-3-methoxythienoic|3,2-syquinolin-4(5H)-one trifluoroacetate

What (6) and; / h

M M j xx OMe i, M 6)

In SEZSO, N

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 103 and 1-(1,3-benzodioxol-5-ylmethyl)piperazine.

РХ/МС 534 (М.Н).

Example 273

Preparation of M-(2-(dimethylamino)ethyl|-3-methoxy-4-oxo-5-(pyridin-2-ylmethyl)-4,5-dihydrothienoi3,2-syquinoline-2-carboxamide ditrifluoroacetate

Me,

M-Me (c); ,i-

M j xx OMe

Mo oh

AM 2 SES

By a method similar to the method given in Example 3, the title compound was obtained from the compound of Auxiliary Example 19 and M,M-dimethylethane-1 2-diamine.

РХ/МС 437 (М.Н).

Example 274

Preparation of 3-methoxy-4-oxo-M,B-bis(pyridin-2-ylmethyl)-4,5-dihydrothienoi|3,2-c)quinoline-2-carboxamide ditrifluoroacetate y-O un

R xx OMe

M (F)

Co

M 2 SEZSO,N

By a method similar to that given in Example C, the title compound was obtained from the compound of Auxiliary Example 19 and 1-pyridin-2-ylmethanamine.

РХ/МС 457 (MN).

Example 275

Preparation of 3-methoxy-4-oxo-5-(pyridin-2-ylmethyl)-M-(pyridin-4-ylmethyl)-4,5-dihydrothienoi3,2-syquinoline-2-carboxamide ditrifluoroacetate in O

M M i shkh s OMe

M (F) x

M 2 СЕ3СО,Н

By a method similar to that given in Example 3, the title compound was obtained from the compound of Auxiliary Example 19 and 1-pyridin-4-ylmethanamine.

РХ/МС 457 (MN).

Example 276

Preparation of // 3-methoxy-4-oxo-5-(pyridin-2-ylmethyl)-M-(2-pyrrolidin-1-ylethyl)-4,5-dihydrothienoi|3,2- syquinoline-2-carboxamide ditrifluoroacetate c (6) ,- their x

HU OMe

M (c);

Co

AM 2 SSO

By a method similar to the method given in Example 3, the title compound was obtained from the compound of Auxiliary Example 19 and 2-pyrrolidin-1-ylethanamine.

РХ/МС 463 (М--Н).

Example 277

Preparation of 3-methoxy-4-oxo-N-(2-pyridin-3-ylethyl)-5-(pyridin-2-ylmethyl)-4,5-dihydrothienoic acid 3,2-siquinoline-2-carboxamide ditrifluoroacetate ich / M at)

M

R with OMe

I. SHY is) ex

AM 2 SSO

By a method similar to the method given in Example C, the title compound was obtained from the compound of Auxiliary Example 19 and 2-pyridin-3-ylethanamine.

РХ/МС 471 (М.Н).

Example 278

Preparation of 3-methoxy-N-(5-methylpyrazin-2-yl)methyl)-4-oxo-5-(pyridin-2-ylmethyl)-4,5-dihydrothienoyl3,2-quinoline-2-carboxamide ditrifluoroacetate -M (in); JAA-KOI-me "Well, xx OMe

I. Shk o)

Co

DM 2 SES,

By a method similar to the method given in Example 3, the title compound was obtained from the compound of Auxiliary Example 19 and 1-(5-methylpyrazin-2-yl)umethanamine.

РХ/МС 472 (М.Н).

Example 279

Preparation of N-3-(1H-imidazol-1-yl)propyl|-3-methoxy-4-oxo-5-(pyridin-2-ylmethyl)-4,5-dihydrothienoyl3,2-quinoline-2-carboxamide ditrifluoroacetate

M

M zh OMe

I. MF)

Co

M 2 SE.SO,N

By a method similar to the method given in Example 3, the title compound was obtained from the compound of Auxiliary Example 19 and 3-(1H-imidazol-1-yl)upropan-1-amine.

РХ/МС 474 (М.Н).

Example 280

Preparation of 3-methoxy-N-(2-(1-methylpyrrolidin-2-yl)ethyl|-4-oxo-5-(pyridin-2-ylmethyl)-4,5-dihydrothienoyl3,2-quinoline-2-carboxamide ditrifluoroacetate

M, oh Me

M j xx OMe

Mo x

AM 2 SSO

By a method similar to that given in Example C, the title compound was obtained from the compound of Auxiliary Example 19 and 2-(1-methylpyrrolidin-2-yl)ethanamine.

РХ/МС 477 (М.Н).

Example 281

Preparation of /3-methoxy-4-oxo-N-(2-piperidin-1-ylethyl)-5-(pyridin-2-ylmethyl)-4,5-dihydrothienoic|3,2-syquinoline-2-carboxamide ditrifluoroacetate (0 ; (o) ,P-

M zh OMe

I. shk c) oh

AM 2 SE.SO,N

By a method similar to the method given in Example 3, the title compound was obtained from the compound of Auxiliary Example 19 and 2-piperidin-1-ylethanamine.

РХ/МС 477 (М.Н).

Example 282

Preparation of /M-|3-(diethylamino)propyl|-3-methoxy-4-oxo-5-(pyridin-2-ylmethyl)-4,5-dihydrothienoic|3,2-syquinoline-2-carboxamide ditrifluoroacetate

IS

Edited by Ei

M

R with OMe

And M); Oh

M 2 SEZSO,N

By a method similar to that given in Example 3, the title compound was obtained from the compound of Auxiliary Example 19 and M,M-diethylpropane-1,3-diamine.

РХ/МС 479 (М.Н).

Example 283

Preparation of 3-methoxy-M-(3-morpholin-4-ylpropyl)-4-oxo-5-(pyridin-2-ylmethyl)-4,5-dihydrothieno|3,2- sequinoline-2-carboxamide ditrifluoroacetate

M c) about /-х/

M

GC with OMe

I. shk c) xx

AM 2 SSO

By a method similar to that given in Example C, the title compound was obtained from the compound of Auxiliary Example 19 and 3-morpholin-4-ylpropan-1-amine.

РХ/МС 493 (М.Н).

Example 284

Preparation of 3-methoxy-N-(3-(4-methylpiperazin-1-yl)propyl|-4-oxo-5-(pyridin-2-ylmethyl)-4,5-dihydrothienoyl-3,2-siquinoline-2-carboxamide tritrifluoroacetate

M M-Me about /-x

M

I'm sorry

I MF)

Su

M Z SEZSON

By a method similar to that given in Example 3, the title compound was obtained from the compound of Auxiliary Example 19 and 3-(4-methylpiperazin-1-yl)/propan-1-amine.

Example 285

Preparation of N-(4-(diethylamino)-1-methylbutyl|-33-methoxy-4-oxo-5-(pyridin-2-ylmethyl)-4,5-dihydrothienoyl-3,2-quinoline-2-carboxamide ditrifluoroacetate

EC

M-EI

Me (about);

M

R xx OMe

M (c); xx

AM 2 Sg, SO, N

By a method similar to the method given in Example 3, the title compound was obtained from the compound of Auxiliary Example 19 and M',M'-diethylpentane-1 4-diamine.

РХ/МС 507 (МН).

Example 286

Preparation of N-(1-benzylpyrrolidin-3-yl)-3-methoxy-4-oxo-5-(pyridin-2-ylmethyl)-4,5-dihydrothienoyl3,2-siquinoline-2-carboxamide ditrifluoroacetate

M

(F)

M

HU OMe

M (c); . m 2 SE.SON

By a method similar to that given in Example C, the title compound was obtained from the compound of Auxiliary Example 19 and 1-benzylpyrrolidin-3-amine.

РХ/МС 525 (МН).

Example 287

Preparation of N-(1-benzylpiperidin-4-yl)-3-methoxy-4-oxo-5-(pyridin-2-ylmethyl)-4,5-dihydrothienoyl3,2-quinoline-2-carboxamide ditrifluoroacetate

M and shk,

M

R xx OMe

M (F)

Wow m 2 CE3SON

By a method similar to the method given in Example 3, the title compound was obtained from the compound of Auxiliary Example 19 and 1-benzylpiperidine-4-amine.

РХ/МС 539 (М.Н).

Example 288

Preparation of 3-methoxy-N-methyl-N-(1-methylpyrrolidin-3-yl)-4-oxo-5-(pyridin-2-ylmethyl)-4,5-dihydrothienoyl3,2-quinoline-2-carboxamide ditrifluoroacetate m " Me o)

M x Me xx OMe

M (6) with

M g SRZ3SON

By a method similar to that given in Example 3, the title compound was obtained from the compound of Auxiliary Example 19 and M, 1-dimethylpyrrolidine-3-amine.

Example 289

Preparation of ditrifluoroacetate

GF) utmMe

M

WITH

H

I. M c)

Su

M 2sgsoN

By a method similar to that given in Example 3, the title compound was obtained from the compound of Auxiliary Example 19 and 1-methyl-1,4-diazepane.

Example 290

Preparation of /-2-((4-ethylpiperazin-1-yl)/ucarbonyl|-3-methoxy-5-(pyridin-2-ylmethyl)uthieno|3,2-c)quinolin-4(5H)-one ditrifluoroacetate 9 ); / Kh

M M-EI e Mch

Their with OMe

And M);

So hak 2 SSO

By a method similar to that given in Example C, the title compound was obtained from the compound of Auxiliary Example 19 and 1-ethylpiperazine.

Example 291

Preparation of 3-methoxy-5-(pyridin-2-ylmethyl)-2-((25)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)carbonyluthieno|3,2-c)quinoline-4(5H )-one ditrifluoroacetate

TV, i o) i m

WITH

X with OMe

I MF)

Co 2M 2 sgsoOH

By a method similar to that given in Example 3, the title compound was obtained from the compound of Auxiliary Example 19 and 1-(25)-pyrrolidin-2-ylmethyl|pyrrolidine.

РХ/МС 503 (М--Н).

Example 292

Preparation of /3-methoxy-5-(pyridin-2-ylmethyl)-2-(4-pyrrolidin-1-ylpiperidin-1-yl)ucarbonyl|hyeno|3,2-syquinolin-4(5H)-one ditrifluoroacetate (6 ) where

WITH

X xx OMe

I. MF) oh

DM 2g SEASON

By a method similar to that given in Example 3, the title compound was obtained from the compound of Auxiliary Example 19 and 4-pyrrolidin-1-ylpiperidine.

РХ/МС 503 (М--Н).

Example 293

Preparation of 3-methoxy-2-(4-phenylpiperazin-1-ylcarbonyl|-5-(pyridin-2-ylmethyl)uthieno|3,2-c)quinolin-4(5H)-one ditrifluoroacetate and; 7 x

М M х сх ОМе

I. MF) sch

AM 2g SES

By a method similar to the method given in Example 3, the title compound was obtained from the compound of Auxiliary Example 19 and 1-phenylpiperazine.

РХ/МС 511 (М--Н).

Example 294

Preparation of M-(2-cyanoethyl)-3-methoxy-4-oxo-5-(pyridin-2-ylmethyl)-M-(pyridin-3-ylmethyl)-4,5-dihydrothienoyl3,2-quinoline-2-carboxamide ditrifluoroacetate

CM o); ;

M -M i KI with OME

I. M c) xx

M 2 SEZSO,N

By a method similar to that given in Example 3, the title compound was obtained from the compound of Auxiliary Example 19 and 3-pyridin-3-ylmethyl)amino|ipropanenitrile.

РХ/МС 510 (М--Н).

Example 295

Preparation of 3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-M-(pyridin-2-ylmethyl)-4,5-dihydrothienoic trifluoroacetate 3,2-syquinoline-2-carboxamide

IN

"Zh

R with OMe

I. Shk o) (6)

SEZSO, N

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 7 and 1-pyridin-2-ylmethanamine.

РХ/МС 484 (М.Н).

Example 296

Preparation of 3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-M-(pyridin-4-ylmethyl)-4,5-dihydrothienoi|3,2-syquinoline-2-carboxamide trifluoroacetate a;

We are still with OMe

I. shk c) c)

SRZSO, N

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 7 and 1-pyridin-4-ylmethanamine.

РХ/МС 484 (М.Н).

Example 297

Preparation of 3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-M-(2-pyridin-3-ylethyl)-4,5-dihydrothienoic acid trifluoroacetate 3,2-siquinoline-2-carboxamide / M c)

M still with OMe

I MF) (c)

SeSO, N

By a method similar to the method given in Example 5, the title compound was obtained from the compound of Auxiliary Example 7 and 2-pyridine-3-ylethanamine.

РХ/МС 498 (М.Н).

Example 298

Preparation of 3-methoxy-N-(5-methylpyrazin-2-yl)methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoyl-3,2-siquinoline-2-carboxamide trifluoroacetate - M (c); I-KOY-me "Well, with OMe

I. M is) (6)

SE.SO,N

By a method similar to the method given in Example 5, the title compound was obtained from the compound of Auxiliary Example 7 and 1-(5-methylpyrazin-2-yl)umethanamine.

РХ/МС 499 (М.Н).

Example 299

Preparation of trifluoroacetate

In /t ha, g s OMe

M (c); (in);

SEZSO, N

By a method similar to the method given in Example 5, the title compound was obtained from the compound of Auxiliary Example 7 and 1-phenylpiperazine.

РХ/МС 538 (М.Н).

Example 300

Preparation of 3-(benzyloxy)-M, 5-dimethyl-4-oxo-4,5-dihydrothieno|3,2-c)quinoline-2-carboxamide c) Me

M j xx o) yo 7

Me

To a solution (0.15 M, 0.40 ml, 60 μmol) of the compound of Auxiliary Example 91 in DMF was added a solution (0.66 M, 0.10 ml, 66 μmol) of methanamine (2.0 M solution in THF) in DMF and a solution (0.39 M, 0.20 ml, 78 μmol) of NOVI and MUZSO in a 1:11 mixture in DMF. The resulting mixture was shaken at room temperature for 14 hours. Dichloromethane (2 mL) and a saturated aqueous solution of sodium hydrogencarbonate (1 mL) were added to the reaction mixture, the organic layer was filtered through a Teflon filter (registered trademark) to separate the aqueous layer, and the filtrate was concentrated under reduced pressure.

The residue was purified by preparative HPLC to give the title compound (12.4 mg, 55 U).

РХ/МС 379 (М.Н).

Example 301

Preparation of 3-(benzyloxy)-N-butyl-5-methyl-4-oxo-4,5-dihydrothieno|3,2-c)quinoline-2-carboxamide

Me o; ped

R xx F) o;

Me

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 91 and butan-1-amine.

РХ/МС 421 (МН).

Example 302

Preparation of 3-(benzyloxy)-M-(furan-2-ylmethyl)-5-methyl-4-oxo-4,5-dihydrothienoic|3,2-c|quinoline-2-carboxamide about K-G and (c) g shxh (in)

M (in) -

Me

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 91 and 1-furan-2-ylmethanamine.

РХ/МС 445 (М.Н).

Example 303

Preparation of 3-(benzyloxy)-5-methyl-4-oxo-N-(tetrahydrofuran-2-ylmethyl)-4,5-dihydrothienoic|3,2-syquinoline-2-carboxamide from yuca (c)

R xx (c)

M (in) -

Me

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 91 and 1-(tetrahydrofuran-2-yl)methanamine.

РХ/МС 449 (М.Н).

Example 304

Preparation of 3-(benzyloxy)-5-methyl-4-oxo-M-(2-phenylethyl)-4,5-dihydrothieno|3,2-c|quinoline-2-carboxamide

And U

M g x F)

M F) -

Me

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 91 and 2-phenylethanamine.

РХ/МС 469 (М--Н).

Example 305

Preparation of 3-(benzyloxy)-M-(2-methoxybenzyl)-5-methyl-4-oxo-4,5-dihydrothienoic|3,2-c|quinoline-2-carboxamide

(in,

M

With x Nmeo same (in,

M (in, -2

Me

By a method similar to the method given in Example 5, the title compound was obtained from the compound of Auxiliary Example 91 and 1-(2-methoxyphenyl)methanamine.

РХ/МС 485 (INN).

Example 306

Preparation of 3-(benzyloxy)-5-methyl-4-oxo-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-4,5-dihydrothienoyl3,2-sequinoline-2-carboxamide h

Y Z

R xx (v, yo 7

Me

By a method similar to the method given in Example 5, the title compound was obtained from the compound of Auxiliary Example 91 and 1,2,3,4-tetrahydronaphthalene-1-amine.

РХ/МС 495 (МН).

Example 307

Preparation of M-(1,3-benzodioxol-5-ylmethyl)-3-(benzyloxy)-5-methyl-4-oxo-4,5-dihydrothienoi|3,2- syquinolin-2-carboxamide - o (F) them

R

ХУ (in)

M (in) -2

Me

By a method similar to the method given in Example 5, the title compound was obtained from the compound of Auxiliary Example 91 and 1-(1,3-benzodioxol-5-ylumethanamine).

РХ/МС 499 (МН).

Example 308

Preparation of 3-(benzyloxy)-M,M-diethyl-5-methyl-4-oxo-4,5-dihydrothienoiZ,2-si|quinoline-2-carboxamide

(6) EE

M x E

ХУ (in) "o

Me

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 91 and M-ethylethanamine.

РХ/МС 421 (М.Н).

Example 309

Preparation of 3-(benzyloxy)-5-methyl-2-(piperidin-1-ylcarbonyl)thieno|3,2-c|quinolin-4(5H)-one)

THEN,

R with F)

M F) -7

Me

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 91 and piperidine.

РХ/МС 433 (INN).

Example 310

Preparation of 3-(benzyloxy)-M-(2-methoxyethyl)-M, 5-dimethyl-4-oxo-4,5-dihydrothieno|3,2-c|quinoline-2-carboxamide

ОМе о 0/Й-

M

Z x Me hu F)

M F) -

Me

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 91 and 2-methoxy-M-methylethanamine.

РХ/МС 437 (INN).

Example 311

Preparation of 3-(benzyloxy)-M-methoxy-M,B-dimethyl-4-oxo-4,5-dihydrothienoiZ,2-c|quinoline-2-carboxamide

O / OMe

Мх Ме шхх о по и

Me

By a method similar to that of Example 335, the title compound was prepared from the compound of Auxiliary Example 91 and M-methoxymethanamine hydrochloride.

РХ/МС 409 (М.Н).

Example 312

Preparation of 3-(benzyloxy)-5-methyl-2-(thiomorpholin-4-ylcarbonyl)thieno|3Z,2-c|quinolin-4(5H)-one 6) / x

M. Z

R xu F)

M F) -2

Me

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 91 and thiomorpholine.

РХ/МС 451 (М.Н).

Example 313

Preparation of 3-(benzyloxy)-2-((28)-2-(methoxymethyl)pyrrolidin-1-ylcarbonyl)-5-methylthienoi|3,2- sequinolin-4(5H)-one

Ωe (in)

M

R f (c)

M (in) -2

Me

By a method similar to the method given in Example 5, the title compound was obtained from the compound of Auxiliary Example 91 and (2K)-2-(methoxymethyl)pyrrolidine.

РХ/МС 463 (INN).

Example 314

Preparation of M-benzyl-3-(benzyloxy)-M,B-dimethyl-4-oxo-4,5-dihydrothienoiZ,2-s|quinoline-2-carboxamide h c.

M x Me same o

Mine;

Me

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 91 and M-methyl-1-phenylmethanamine.

РХ/МС 469 (М--Н).

Example 315

Preparation of 3-(benzyloxy)-5-methyl-M,M-bis(2-methylpropyl)-4-oxo-4,5-dihydrothieno|3,2-c|quinoline-2-carboxamide

Me

Me (in;

M Me 5-4 - ho o Me

M (in, -

Me

By a method similar to that of Example 335, the title compound was prepared from the compound of Auxiliary Example 91 and 2-methyl-N-(2-methylpropyl)propan-1-amine hydrochloride.

РХ/МС 477 (М.Н).

Example 316

Preparation of 3-(benzyloxy)-M-3-(dimethylamino)propyl|-5-methyl-4-oxo-4,5-dihydrothienoic|3,2-syquinoline-2-carboxamide trifluoroacetate

Me 7

M o /-/ Me i

R c c)

M c) -3

Me sv,so,N

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 91 and M,M-dimethylpropane-1,3-diamine.

РХ/МС 450 (М--Н).

Example 317

Preparation of trifluoroacetate 3-(benzyloxy)-M-(2-(diethylamino)ethyl|-5-methyl-4-oxo-4,5-dihydrothieno|3,2-c|quinoline-2-carboxamide

EC

M-E (c) No-

M still xx (in,

Min); -

Me

SE.SO,N

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 91 and M,M-diethylethane-1 2-diamine.

РХ/МС 464 (М.Н).

Example 318

Preparation of trifluoroacetate 3-(benzyloxy)-M-I(3-(1H-imidazol-1-yl)propyl|-5-methyl-4-oxo-4,5-dihydrothieno|3,2-syquinoline-2-carboxamide -td-e

MO o red heh

She

R s )

M) -

Me se,so,n

By a method similar to the method given in Example 5, the title compound was obtained from the compound of Auxiliary Example 91 and 3-(1H-imidazol-1-yl)upropan-1-amine.

РХ/МС 473 (МН).

Example 319

Preparation of trifluoroacetate 3-(benzyloxy)-M-(2-|bis(1-methylethyl)amino|ethyl)-5-methyl-4-oxo-4,5-dihydrothienoic-3,2-syquinoline-2-carboxamide

Me

Me-X Me m- (v, ,Y- Me

She

X xx (F)

M (F) -

Me se, SsO, Nn

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 91 and M,M-bis(1-methylethyl)ethane-1,2-diamine.

РХ/МС 492 (INN).

Example 320

Preparation of 3-(benzyloxy)-5-methyl-2-((4-methylpiperazin-1-yl)carbonyligieno|3,2-c|quinolin-4(5H)-one trifluoroacetate

M M-Me x /

R c c) yo 7

Me se, soN

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 91 and 1-methylpiperazine.

РХ/МС 448 (М.Н).

Example 321

Preparation of / 3-(benzyloxy)-M, 5-dimethyl-M-(1-methylpyrrolidin-3-yl)-4-oxo-4,5-dihydrothienoi|3,2- sequinoline-2-carboxamide trifluoroacetate m7Me o

M x Me s o)

M F) -

Me

SE.SO,N

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 91 and M, 1-dimethylpyrrolidine-3-amine.

РХ/МС 462 (МН).

Example 322

Preparation of trifluoroacetate 3-(benzyloxy)-M-(2-(diethylamino)ethyl||-M,B-dimethyl-4-oxo-4,5-dihydrothienoic3,2-syquinoline-2-carboxamide

IS;,

M-EI o 0/Й-

M

5 X Me

In oh oh

Me se, soNn

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 91 and M,M-diethyl-M'-methylethane-1,2-diamine.

РХ/МС 478 (INN).

Example 323

Preparation of 3-(benzyloxy)-5-methyl-2-(4-pyridin-2-ylpiperazin-1-yl)ucarbonyligieno|3,2-c|quinolin-4(5H)-one trifluoroacetate (6) /ltUu M- -

M M s M -/

H

HU (in,

M (c); -

Me

SE, SO, N

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 91 and 1-pyridin-2-ylpiperazine.

РХ/МС 511 (М.Н).

Example 324

Preparation of 3-butoxy-M, 5-dimethyl-4-oxo-4,5-dihydrothienoi3,2-siquinoline-2-carboxamide o, Me

M

HU sho them about Me

Me

By a method similar to that of Example 300, the title compound was prepared from the compound of Auxiliary Example 92 and methanamine (2.0 M solution in THF).

РХ/МС 345 (INN).

Example 325

Preparation of 3-butoxy-N-butyl-5-methyl-4-oxo-4,5-dihydrothieno|3,2-s|quinoline-2-carboxamide

Me o; ed

R

Yes (in, their oh what

Me

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 92 and butan-1-amine.

РХ/МС 387 (INN).

Example 326

Preparation of 3-butoxy-M-(furan-2-ylmethyl)-5-methyl-4-oxo-4,5-dihydrothieno|3,2-s|quinoline-2-carboxamide by 1st (c)

R s (c) her o y

Me

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 92 and 1-furan-2-ylmethanamine.

РХ/МС 411 (МН).

Example 327

Preparation of 3-butoxy-5-methyl-4-oxo-N-(tetrahydrofuran-2-ylmethyl)-4,5-dihydrothieno|3,2-c)quinoline-2-carboxamide about t-

M o

R h o their o what

Me

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 92 and 1-(tetrahydrofuran-2-yl)methanamine.

РХ/МС 415 (М.Н).

Example 328

Preparation of 3-butoxy-5-methyl-4-oxo-M-(2-phenylethyl)-4,5-dihydrothieno|3,2-c|quinoline-2-carboxamide

M j xx )

I; about and

Me

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 92 and 2-phenylethanamine.

РХ/МС 435 (М.Н).

Example 329

Preparation of 3-butoxy-M-(2-methoxybenzyl)-5-methyl-4-oxo-4,5-dihydrothieno|3,2-s|quinoline-2-carboxamide

(in)

M x Nmeo

HU (6) her about and

Me

By a method similar to the method given in Example 5, the title compound was obtained from the compound of Auxiliary Example 92 and 1-(2-methoxyphenyl)methanamine.

РХ/МС 451 (М.Н).

Example 330

Preparation of 3-butoxy-5-methyl-4-oxo-M-(1,2,3,4-tetrahydronaphthalen-1-yl)-4,5-dihydrothieno|3,2- sequinoline-2-carboxamide

K her and х хх (in) mo M

Me

By a method similar to the method given in Example 5, the title compound was obtained from the compound of Auxiliary Example 92 and 1,2,3,4-tetrahydronaphthalene-1-amine.

РХ/МС 461 (М.Н).

Example 331

Preparation of M-(1,3-benzodioxol-5-ylmethyl)-3-butoxy-5-methyl-4-oxo-4,5-dihydrothieno|3,2-c)quinoline-2-carboxamide) (F) eat

R xx o

Me

By a method similar to the method given in Example 5, the title compound was obtained from the compound of Auxiliary Example 92 and 1-(1,3-benzodioxol-5-ylumethanamine).

РХ/МС 465 (М.Н).

Example 332

Preparation of 3-butoxy-M,M-diethyl-5-methyl-4-oxo-4,5-dihydrothienoi3,2-c|quinoline-2-carboxamide

M x E same (in) their o sho

Me

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 92 and M-ethylethanamine.

РХ/МС 387 (INN).

Example 333

Preparation of 3-butoxy-5-methyl-2-(piperidin-1-ylcarbonyl)thieno|3,2-c|quinolin-4(5H)-one

F) t,

R z F) their o y

Me

By a method similar to the method given in Example 5, the title compound was obtained from the compound of Auxiliary Example 92 and piperidine.

РХ/МС 399 (INN).

Example 334

Preparation of 3-butoxy-M-(2-methoxyethyl)-M,B-dimethyl-4-oxo-4,5-dihydrothienoic|3,2-c|quinoline-2-carboxamide

ОМе о 0/Й-

M

5 X Me

What's wrong with her?

Me

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 92 and 2-methoxy-M-methylethanamine.

РХ/МС 403 (INN).

Example 335

Preparation of 3-butoxy-M-methoxy-M, 5-dimethyl-4-oxo-4,5-dihydrothienoi3,2-siquinoline-2-carboxamide

O / OMe

M x Me s (b) their o what

Me

To a solution (0.15 M, 0.40 ml, 60 μmol) of the compound of Auxiliary Example 92 in DMF was added a mixture of a suspension (0.66 M, 0.111 ml, 73 μmol) of M-methoxymethanamine hydrochloride in DMF and triethylamine (10.9 μl , 78 μmol), and a solution (0.39 M, 0.20 ml, 78 μmol) of NOVI and MUZSO in a 1:11 mixture in DMF. The resulting mixture was shaken at room temperature for 14 hours. Dichloromethane (2 mL) and a saturated aqueous solution of sodium hydrogencarbonate (1 mL) were added to the reaction mixture, the organic layer was filtered through a Teflon filter (registered trademark) to separate the aqueous layer, and the filtrate was concentrated under reduced pressure. The residue was purified with the help of preparative

HPLC to give the title compound (16.6 mg, 74 95).

РХ/МС 375 (М.Н).

Example 336

Preparation of 3-butoxy-5-methyl-2-(thiomorpholin-4-ylcarbonyl)thieno|3,2-cyquinolin-4(5H)-one 8) 7 X

M Z same sx c)

I; oh shoi

Me

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 92 and thiomorpholine.

РХ/МС 417 (М.Н).

Example 337

Preparation of 3-butoxy-2-((2H8)-2-(methoxymethyl)pyrrolidin-1-ylcarbonyl)-5-methylthieno|3,2-c)quinolin-4(5H)-one

OMe )

M

MORE xx F) to them o shoi

Me

By a method similar to the method given in Example 5, the title compound was obtained from the compound of Auxiliary Example 92 and (2K)-2-(methoxymethyl)pyrrolidine.

РХ/МС 429 (М.Н).

Example 338

Preparation of M-benzyl-3-butoxy-M, 5-dimethyl-4-oxo-4,5-dihydrothieno|3,2-quinoline-2-carboxamide

In the village

M x Me what in

And oh shy

Me

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 92 and M-methyl-1-phenylmethanamine.

РХ/МС 435 (М.Н).

Example 339

Preparation of 3-butoxy-5-methyl-M, /M-bis(2-methylpropyl)-4-oxo-4,5-dihydrothieno|3,2-s|quinoline-2-carboxamide

Me

Me o)

M Me

With -yayu schu t! Me eat o shoi

Me

By a method similar to that of Example 335, the title compound was prepared from the compound of Auxiliary Example 92 and 2-methyl-N-(2-methylpropyl)propan-1-amine hydrochloride.

РХ/МС 443 (М.Н).

Example 340

Preparation of /3-butoxy-N-3-(dimethylamino)propyl|-5-methyl-4-oxo-4,5-dihydrothienoi3,2-c|quinoline-2-carboxamide trifluoroacetate

Me 7

Mo; Ed

Me se, soOn

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 92 and M,M-dimethylpropane-1,3-diamine.

РХ/МС 416 (М.Н).

Example 341

Preparation of 3-butoxy-M-(2-(diethylamino)ethyl|-5-methyl-4-oxo-4,5-dihydrothienoic|3,2-c|quinoline-2-

trifluoroacetate carboxamide

hey

M-EI o 0/Й-

her

R and c)

I; oh and

Me se, dream

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 92 and M,M-diethylethane-1 2-diamine.

РХ/МС 430 (INN).

Example 342

Preparation of trifluoroacetate trifluoroacetate 3-butoxy-M-I(3-(1H-imidazol-1-yl)/propyl|-5o-methyl-4-oxo-4,5-dihydrothienoi3,2-c|quinoline-2-carboxamide th

R z d) her o y

Me

SESO, N

By a method similar to the method given in Example 5, the title compound was obtained from the compound of Auxiliary Example 92 and 3-(1H-imidazol-1-yl)upropan-1-amine.

РХ/МС 439 (INN).

Example 343

Preparation of trifluoroacetate M-2-(bis(1-methylethyl)amino|ethyl)-3-butoxy-5-methyl-4-oxo-4,5-dihydrothieno|3,2-syquinoline-2-carboxamide

Me

Me-- Me m- o 0/-- Me

Her x hu c)

I am

Me se,so,n

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 92 and M,M-bis(1-methylethyl)ethane-1,2-diamine.

РХ/МС 458 (INN).

Example 344

Preparation of 3-butoxy-5-methyl-2-((4-methylpiperazin-1-yl)ucarbonyligieno-3,2-c|quinolin-4(5H)-one trifluoroacetate o / x

M M-Me

From -07-

X xx o) her o shoi

Me

SEzSO, N

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 92 and 1-methylpiperazine.

РХ/МС 414 (М.Н).

Example 345

Preparation of 3-butoxy-M, 5-dimethyl-M-(1-methylpyrrolidin-3-yl)-4-oxo-4,5-dihydrothieno|3,2-c)quinoline-2-carboxamide trifluoroacetate -M

M e (in;

M

X Me xx (in,

That's about it

Me sv,sO,N

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 92 and M, 1-dimethylpyrrolidine-3-amine.

РХ/МС 428 (INN).

Example 346

Preparation of trifluoroacetate 3-butoxy-M-(2-(diethylamino)ethyl|-M,5-dimethyl-4-oxo-4,5-dihydrothieno|III,2-c|quinoline-2-carboxamide

IS.,

M-EI at 0/-

M

Z x Me

ХУ c)

I; oh and

Me se, soO, N

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 92 and M,M-diethyl-M'-methylethane-1,2-diamine.

РХ/МС 444 (М.Н).

Example 347

Preparation // 3-butoxy-5-methyl-2-(4-pyridin-2-ylpiperazin-1-yl)ucarbonyl|hyenoY3,2-c|quinolin-4(5H)-one trifluoroacetate

O 0/- M-

M M x / in,

R

Shh (c)

Oh shoi

Me seg, soON

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 92 and 1-pyridin-2-ylpiperazine.

РХ/МС 477 (М.Н).

Example 348

Preparation of M, 5-dimethyl-4-oxo-3-(pyridin-4-ylmethoxy)-4,5-dihydrothienoyl-3,2-c|quinoline-2-carboxamide trifluoroacetate o Me

It's all about it)

Shi

M7sO A

Me

SRZSON

To a solution (0.10 M, 0.40 ml, 40 μmol) of the compound of Auxiliary Example 93 in DMF was added a solution (0.66 M, 0.10 ml, 66 μmol) of methanamine (2.0 M solution in THF) in DMF and a solution (0.39 M, 0.20 ml, 78 μmol) of NOVI and MUZSO in a 1:11 mixture in DMF. The resulting mixture was shaken at room temperature for 14 hours. Dichloromethane (2 mL) and a saturated aqueous solution of sodium hydrogencarbonate (1 mL) were added to the reaction mixture, the organic layer was filtered through a Teflon filter (registered trademark) to separate the aqueous layer, and the filtrate was concentrated under reduced pressure.

The residue was purified by preparative HPLC to give the title compound (13.2 mg, 67 U).

РХ/МС 380 (М--Н).

Example 349

Preparation of trifluoroacetate M-butyl-5-methyl-4-oxo-3-(pyridin-4-ylmethoxy)-4,5-dihydrothieno|3,2-c|quinoline-2-carboxamide

Me o; ed

R xx ) -"ku mya m

Me se, soN

To a solution (0.10 M, 0.40 ml, 40 μmol) of the compound of Auxiliary Example 93 in DMF was added a solution (0.66 M, 0.10 ml, 66 μmol) of butan-1-amine in DMF and a solution (0. 39 M, 0.20 ml, 78 μmol) NEW i

MIZSO in a mixture of 1:11 in DMF. The resulting mixture was shaken at room temperature for 14 hours.

Dichloromethane (2 mL) and a saturated aqueous solution of sodium hydrogencarbonate (1 mL) were added to the reaction mixture, the organic layer was filtered through a Teflon filter (registered trademark) to separate the aqueous layer, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (13.5 mg, 63 Vol).

РХ/МС 422 (МН).

Example 350

Preparation of M-(furan-2-ylmethyl)-5-methyl-4-oxo-3-(pyridin-4-ylmethoxy)-4,5-dihydrothieno|3,2-syquinoline-2-carboxamide trifluoroacetate about K-H

M o sh xx o) -yIyaIf

M

M (in) -

Me se, soO, N

By a method similar to that given in Example 349, the title compound was obtained from the compound of Auxiliary Example 93 and 1-furan-2-ylmethanamine.

РХ/МС 446 (М.Н).

Example 351

Preparation of trifluoroacetate 5-methyl-4-oxo-3-(pyridin-4-ylmethoxy)-N-(tetrahydrofuran-2-ylmethyl)-4,5-dihydrothienoyl3,2-siquinoline-2-carboxamide

M o z xx 6) --f3.

M

M c) -th

Me sv,soON

By a method similar to that of Example 349, the title compound was obtained from the compound of Auxiliary Example 93 and 1-(tetrahydrofuran-2-yl)methanamine.

РХ/МС 450 (М--Н).

Example 352

Preparation of trifluoroacetate 5-methyl-4-oxo-N-(2-phenylethyl)-3-(pyridin-4-ylmethoxy)-4,5-dihydrothienoic 3,2-c|quinoline-2-carboxamide

She still xx F) -iou

M7bSo what;

AND

Me

SE.SO,N

By a method similar to that of Example 349, the title compound was prepared from the compound of Auxiliary Example 93 and 2-phenylethanamine.

РХ/МС 470 (М--Н).

Example 353

Preparation of M-(2-methoxybenzyl)-5-methyl-4-oxo-3-(pyridin-4-ylmethoxy)-4,5-dihydrothieno|3,2-c|quinoline-2-carboxamide trifluoroacetate c)

M

Z x Nmeo xx c) pe-

Mm"bZO A

AND

Me

SEZSO, N

By a procedure similar to that of Example 349, the title compound was prepared from the compound of Auxiliary Example 93 and 1-(2-methoxyphenyl)methanamine.

РХ/МС 486 (М.Н).

Example 354

Preparation of 5-methyl-4-oxo-3-(pyridin-4-ylmethoxy)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-4,5-dihydrothienoyl3,2-siquinoline-2-carboxamide trifluoroacetate h

M. Z

ХУ (in) pe-u

Mm'7ZO A

AND

Me

SEZSO, N

By a method similar to that given in Example 349, the title compound was obtained from the compound of Auxiliary Example 93 and 1,2,3,4-tetrahydronaphthalene-1-amine.

РХ/МС 496 (МН).

Example 355

Preparation of M-(1,3-benzodioxol-5-ylmethyl)-5-methyl-4-oxo-3-(pyridin-4-ylmethoxy)-4,5-dihydrothienoyl-3,2-siquinoline-2-carboxamide trifluoroacetate

What is it?

R

ХУ (6) -iu

MO A

AND

Me

SEZSO, N

By a method similar to the method given in Example 349, the title compound was obtained from the compound of Auxiliary Example 93 and 1-(1,3-benzodioxol-5-ylumethanamine).

РХ/МС 500 (INN).

Example 356

Preparation of M, M-diethyl-5-methyl-4-oxo-3-(pyridin-4-ylmethoxy)-4,5-dihydrothienoi3,2-c|quinoline-2-carboxamide trifluoroacetate

M x E xx (v, -e-L mo a

AND

Me

SEZSO, N

By a method similar to that given in Example 349, the title compound was prepared from the compound of Auxiliary Example 93 and M-ethylethanamine.

РХ/МС 422 (МН).

Example 357

Preparation of 5-methyl-2-(piperidin-1-ylcarbonyl)-3-(pyridin-4-ylmethoxy)thieno|3,2-c|quinolin-4(5H)-one trifluoroacetate (6) io,

R sh (c) rn

Ministry of Defense

AND

Me

SE, SO, N

By a method similar to that given in Example 349, the title compound was prepared from the compound of Auxiliary Example 93 and piperidine.

РХ/МС 434 (М.Н).

Example 358

Preparation of M-(2-methoxyethyl)-M, 5-dimethyl-4-oxo-3-(pyridin-4-ylmethoxy)-4,5-dihydrothieno|3,2- syquinoline-2-carboxamide trifluoroacetate

OMe at 00/-

M

X Me xx o) -shshkh

Mo A

AND

Me se, soN

By a procedure similar to that of Example 349, the title compound was prepared from the compound of Auxiliary Example 93 and 2-methoxy-M-methylethanamine.

РХ/МС 438 (М.Н).

Example 359

Preparation of M-methoxy-M, 5-dimethyl-4-oxo-3-(pyridin-4-ylmethoxy)-4,5-dihydrothieno|3,2-c|quinoline-2-carboxamide trifluoroacetate o, ОМе

M

5 X Me xx )

Shu

Mm7ozo what;

Me

SEZSO, N

To a solution (0.10 M, 0.40 ml, 40 μmol) of the compound of Auxiliary Example 93 in DMF was added a mixture of a suspension (0.66 M, 0.111 ml, 73 μmol) of M-methoxymethanamine hydrochloride in DMF and triethylamine (10.9 μl , 78 μmol), and a solution (0.39 M, 0.20 ml, 78 μmol) of NOVI and MUZSO in a 1:1 mixture in DMF. The resulting mixture was shaken at room temperature for 14 hours. Dichloromethane (2 mL) and a saturated aqueous solution of sodium hydrogencarbonate (1 mL) were added to the reaction mixture, the organic layer was filtered through a Teflon filter (registered trademark) to separate the aqueous layer, and the filtrate was concentrated under reduced pressure. The residue was purified with the help of preparative

HPLC to give the title compound (12.3 mg, 59 95).

РХ/МС 410 (М--Н).

Example 360

Preparation of trifluoroacetate 5-methyl-3-(pyridin-4-ylmethoxy)-2-(thiomorpholin-4-ylcarbonyl)thieno|3,2-c|quinolin-4(5H)-one 9) / x

M 5

R xx (in) Mon

Mo them

AND

Me sv,sON

By a method similar to that given in Example 349, the title compound was prepared from the compound of Auxiliary Example 93 and thiomorpholine.

РХ/МС 452 (МН).

Example 361

Preparation of 2-(28)-2-(methoxymethyl)pyrrolidin-1-ylcarbonyl)-5-methyl-3-(pyridin-4-ylmethoxy)thienoyl-3,2-c|quinolin-4(5H)-one trifluoroacetate

OMe )

M

R

HU F) pe-Tso

MO I

AND

Me se, SsO, N

By a method similar to that given in Example 349, the title compound was obtained from the compound of Auxiliary Example 93 and (2K)-2-(methoxymethyl)pyrrolidine.

РХ/МС 464 (М.Н).

Example 362

Preparation of M-benzyl-M, 5-dimethyl-4-oxo-3-(pyridin-4-ylmethoxy)-4,5-dihydrothieno|3,2-c)quinoline-2-carboxamide trifluoroacetate their F

M

X Me

HU (in, - In mo A

AND

Me se, So, N

By a procedure similar to that of Example 349, the title compound was prepared from the compound of Auxiliary Example 93 and M-methyl-1-phenylmethanamine.

РХ/МС 470 (М.Н).

Example 363

Preparation of 5-methyl-M, M-bis(2-methylpropyl)-4-oxo-3-(pyridin-4-ylmethoxy)-4,5-dihydrothieno|3,2-syquinoline-2-carboxamide trifluoroacetate

Me

Me (in)

M Me

R i ho t) Me

Shu

M" A

AND

Me se, sSo, N

By a method similar to that given in Example 359, the title compound was prepared from the compound of Auxiliary Example 93 and 2-methyl-N-(2-methylpropyl)propan-1-amine hydrochloride.

РХ/МС 478 (М.Н).

Example 364

Preparation of M-III-(dimethylamino)propyl-5-methyl-4-oxo-3-(pyridin-4-ylmethoxy)-4,5-dihydrothienoyl3,2-quinoline-2-carboxamide ditrifluoroacetate

Me

Mo; Ed. Me

She

R xx c) pe-

M

M c) -

Me 2 SEsoONn

By a method similar to that given in Example 349, the title compound was obtained from the compound of Auxiliary Example 93 and M,M-dimethylpropane-1,3-diamine.

РХ/МС 451 (М--Н).

Example 365

Preparation of M-(2-(diethylamino)ethyl|-5-methyl-4-oxo-3-(pyridin-4-ylmethoxy)-4,5-dihydrothienoic|3,2-syquinoline-2-carboxamide ditrifluoroacetate

KE

M-EI at 0/-

She

R

have)

Shu m'o eat

Me 2 sE/СО,Н

By a method similar to that given in Example 349, the title compound was obtained from the compound of Auxiliary Example 93 and M,M-diethylethane-1 2-diamine.

РХ/МС 465 (М--Н).

Example 366

Preparation of N-3-(1H-imidazol-1-yl)propyl-5-methyl-4-oxo-3-(pyridin-4-ylmethoxy)-4,5-dihydrothienoyl3,2-quinoline-2-carboxamide ditrifluoroacetate

-esh-;

M o red ha i

X c )

MO A

AND

Me 2 sesoOH

By a method similar to that given in Example 349, the title compound was obtained from the compound of Auxiliary Example 93 and 3-(1H-imidazol-1-yl)upropan-1-amine.

РХ/МС 474 (М.Н).

Example 367

Preparation of M-2-Bis(1-methylethyl)amino|ethyl)-5-methyl-4-oxo-3-(pyridin-4-ylmethoxy)-4,5-dihydrothienoyl3,2-quinoline-2-carboxamide ditrifluoroacetate

Me

Me-( Me m- o 0/-4- Me i

R xh ) pya-- mo

Me 2 SeE, SON

By a method similar to that of Example 349, the title compound was prepared from the compound of Auxiliary Example 93 and M,M-bis(1-methylethyl)ethane-1,2-diamine.

РХ/МС 493 (М.Н).

Example 368

Preparation of 5-methyl-2-|((4-methylpiperazin-1-yl)ucarbonyl|-3-(pyridin-4-ylmethoxy)thieno|3,2-c|quinolin-

A(5H)-one of ditrifluoroacetate o / x

M M-Me

With -

Their s

Shu

Mm'ZO A

Me 2 SeE,soOHn

By a method similar to that of Example 349, the title compound was prepared from the compound of Auxiliary Example 93 and 1-methylpiperazine.

Example 369

Preparation of M, 5-dimethyl-N-(1-methylpyrrolidin-3-yl)-4-oxo-3-(pyridin-4-ylmethoxy)-4,5-dihydrothienoyl3,2-quinoline-2-carboxamide ditrifluoroacetate

"Me

M

(at,

M

X Me xx (in,

Tires mo Hmm

AND

Me 2 SsgEsoNn

By a method similar to the method given in Example 349, the title compound was obtained from the compound of Auxiliary Example 93 and M, 1-dimethylpyrrolidine-3-amine.

Example 370

Preparation of M-(2-(diethylamino)ethyl||-M,B-dimethyl-4-oxo-3-(pyridin-4-ylmethoxy)-4,5-dihydrothieno33,2-c)quinoline-2-carboxamide ditrifluoroacetate

KE

M-EI (F) ,-

M

5 x Me

ХУ c) -yadasu

MO x

She

Me 2 SEASON

By a method similar to that of Example 349, the title compound was prepared from the compound of Auxiliary Example 93 and M,M-diethyl-M'-methylethane-1,2-diamine.

Example 371

Preparation of 5-methyl-3-(pyridin-4-ylmethoxy)-2-(4-pyridin-2-ylpiperazin-1-yl)carbonylene|3,2-syquinolin-4(5H)-one 2 trifluoroacetate

O /;/- mm-

M M s M -/

Same about

Shu mo MM

AND

Me 2 SsE, SON

By a method similar to that of Example 349, the title compound was prepared from the compound of Auxiliary Example 93 and 1-pyridin-2-ylpiperazine.

РХ/МС 512 (М.Н).

Example 372

Preparation of M, 5-dimethyl-3-(2-morpholin-4-ylethoxy)-4-oxo-4,5-dihydrothieno|3,2-c|quinoline-2-carboxamide trifluoroacetate o; Me

M

R skh and mod

Me s svsoNn 9

By a procedure similar to that of Example 349, the title compound was prepared from the compound of Auxiliary Example 94 and methanamine (2.0 M solution in THF).

РХ/МС 402 (М.Н).

Example 373

Preparation of M-butyl-5-methyl-3-(2-morpholine-4-ylethoxy)-4-oxo-4,5-dihydrothieno3,2-c|quinoline-2-carboxamide trifluoroacetate

Me (o; ed

R with M

Mo

Me «s sEzSo,N OTO

By a method similar to that given in Example 349, the title compound was prepared from the compound of Auxiliary Example 94 and butan-1-amine.

РХ/МС 444 (М.Н).

Example 374

Preparation of M-(furan-2-ylmethyl)-5-methyl-3-(2-morpholin-4-ylethoxy)-4-oxo-4,5-dihydrothienoic-3,2-syquinoline-2-carboxamide of trifluoroacetate (in )

R xx M mo

Me "c

SE, so, Nn OO o

By a method similar to that of Example 349, the title compound was prepared from the compound of Auxiliary Example 94 and 1-furan-2-ylmethanamine.

РХ/МС 468 (М--Н).

Example 375

Preparation of trifluoroacetate 5-methyl-3-(2-morpholin-4-ylethoxy)-4-oxo-N-(tetrahydrofuran-2-ylmethyl)-4,5-dihydrothienoyl3,2-siquinoline-2-carboxamide

M c)

R xx M mod

Me "in sEzSo, N Oto

By a method similar to that of Example 349, the title compound was prepared from the compound of Auxiliary Example 94 and 1-(tetrahydrofuran-2-yl)methanamine.

РХ/МС 472 (М.Н).

Example 376

Preparation of trifluoroacetate 5-methyl-3-(2-morpholin-4-ylethoxy)-4-oxo-M-(2-phenylethyl)-4,5-dihydrothienoic|3,2-syquinoline-2-carboxamide

M zh shkh y mo

Me c

SsE.So,NnOoOto

By a method similar to that of Example 349, the title compound was prepared from the compound of Auxiliary Example 94 and 2-phenylethanamine.

РХ/МС 492 (М.Н).

Example 377

Preparation of M-(2-methoxybenzyl)-5-methyl-3-(2-morpholin-4-ylethoxy)-4-oxo-4,5-dihydrothieno|3,2-syquinoline-2-carboxamide trifluoroacetate c)

M

With x Meo hu and mok

Me s sEzso,nN Oto

By a procedure similar to that of Example 349, the title compound was prepared from the compound of Auxiliary Example 94 and 1-(2-methoxyphenyl)methanamine.

РХ/МС 508 (М--Н).

Example 378

Preparation of 5-methyl-3-(2-morpholin-4-ylethoxy)-4-oxo-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-4,5-dihydrothienoyl3,2-siquinoline-2 -trifluoroacetate carboxamide

In her o

Rs and mod

Me c

СсЕ, СО, Н 0

By a method similar to that given in Example 349, the title compound was obtained from the compound of Auxiliary Example 94 and 1,2,3,4-tetrahydronaphthalene-1-amine.

РХ/МС 518 (М--Н).

Example 379

Preparation of trifluoroacetate M-(1,3-benzodioxol-5-ylmethyl)-5-methyl-3-(2-morpholin-4-ylethoxy)-4-oxo-4,5-dihydrothienoyl3,2-siquinoline-2-carboxamide - about (in,

M zh s i

Mom

Me "c

SsE.So,NnOoOto

By a method similar to the method given in Example 349, the title compound was obtained from the compound of Auxiliary Example 94 and 1-(1,3-benzodioxol-5-ylumethanamine).

РХ/МС 522 (М.Н).

Example 380

Preparation of M, M-diethyl-5-methyl-3-(2-morpholin-4-ylethoxy)-4-oxo-4,5-dihydrothieno|3,2-c)quinoline-2-carboxamide trifluoroacetate

M x E

HU and mok

Me (p

SsEzSo, Nn Oto

By a method similar to that given in Example 349, the title compound was prepared from the compound of Auxiliary Example 94 and M-ethylethanamine.

РХ/МС 444 (М.Н).

Example 381

Preparation of trifluoroacetate 5-methyl-3-(2-morpholin-4-ylethoxy)-2-(piperidin-1-ylcarbonyl)thieno|3,2-c|quinolin-4(5H)-one

Mo

Me s seEZSo,nN OO To

By a procedure similar to that of Example 349, the title compound was prepared from the compound of Auxiliary Example 94 and piperidine.

РХ/МС 456 (INN).

Example 382

Preparation of M-(2-methoxyethyl)-M, 5-dimethyl-3-(2-morpholin-4-ylethoxy)-4-oxo-4,5-dihydrothieno|3,2- sequinoline-2-carboxamide trifluoroacetate

OMe at 00/Й-

M

5 X Me

HU and

Mo

Me "c

SSO, Fr

By a procedure similar to that of Example 349, the title compound was prepared from the compound of Auxiliary Example 94 and 2-methoxy-M-methylethanamine.

РХ/МС 460 (М.Н).

Example 383

Preparation of M-methoxy-M, B-dimethyl-3-(2-morpholin-4-ylethoxy)-4-oxo-4,5-dihydrothieno|3,2- sichinoline-2-carboxamide trifluoroacetate

O / OMe

M

Z X Me xx in mo

Me with c)

SEZSO, N

By a procedure similar to that of Example 359, the title compound was prepared from the compound of Auxiliary Example 94 and M-methoxymethanamine hydrochloride.

РХ/МС 432 (М.Н).

Example 384

Preparation of 5-methyl-3-(2-morpholin-4-ylethoxy)-2-(thiomorpholin-4-ylcarbonyl)thieno|3,2-c|quinolin-4(5H)-one trifluoroacetate o / x

M Z x / f x x and mod

Me (In St. SO, N Oto

By a method similar to that of Example 349, the title compound was prepared from the compound of Auxiliary Example 94 and thiomorpholine.

РХ/МС 474 (М.Н).

Example 385

Preparation of trifluoroacetate 2-S(28)-2-(methoxymethyl)pyrrolidin-1-ylcarbonyl)-5-methyl-3-(2-morpholin-4-ylethoxy)thieno|3,2-c|quinolin-4(5H)-one

Ohm c)

M

R

Kh and

Mo

Me s seEZsoO,Nn Oto

By a method similar to that given in Example 349, the title compound was obtained from the compound of Auxiliary Example 94 and (2K)-2-(methoxymethyl)pyrrolidine.

РХ/МС 486 (М.Н).

Example 386

Preparation of M-benzyl-M, 5-dimethyl-3-(2-morpholin-4-ylethoxy)-4-oxo-4,5-dihydrothieno|3,2-c)quinoline-2-carboxamide trifluoroacetate h c.

M x Me

J. M

Mo

Me «) se,so,n OO

By a procedure similar to that of Example 349, the title compound was prepared from the compound of Auxiliary Example 94 and M-methyl-1-phenylmethanamine.

РХ/МС 492 (INN).

Example 387

Preparation of 5-methyl-M, M-bis(2-methylpropyl)-3-(2-morpholin-4-ylethoxy)-4-oxo-4,5-dihydrothienoic-3,2-syquinoline-2-carboxamide trifluoroacetate

Me

Me (about;

M Me 8th - ho and Me

Dan;

Me s) sEzSO,N OTO

By a method similar to that of Example 359, the title compound was prepared from the compound of Auxiliary Example 94 and 2-methyl-N-(2-methylpropyl)propan-1-amine hydrochloride.

РХ/МС 500 (INN).

Example 388

Preparation of M-III-"dimethylamino)propyl-5-methyl-3-(2-morpholin-4-ylethoxy)-4-oxo-4,5-dihydrothienoyl3,2-quinoline-2-carboxamide ditrifluoroacetate

Me

M

(F) ed. Me

She

R xx and

Mo

Me "in 2sEson o

By a method similar to that given in Example 349, the title compound was prepared from the compound of Auxiliary Example 94 and M,M-dimethylpropane-1,3-diamine.

РХ/МС 473 (МН).

Example 389

Preparation of M-(2-(diethylamino)ethyl|-5-methyl-3-(2-morpholin-4-ylethoxy)-4-oxo-4,5-dihydrothienoic|3,2-syquinoline-2-carboxamide ditrifluoroacetate

IS!,

M-E at 0/Х- th

R xx in mok

Me "s 2svSoONn o

By a method similar to that given in Example 349, the title compound was prepared from the compound of Auxiliary Example 94 and M,M-diethylethane-1 2-diamine.

РХ/МС 487 (М.Н).

Example 390

Preparation of M-3-(1H-imidazol-1-yl)propyl|-5-methyl-3-(2-morpholin-4-ylethoxy)-4-oxo-4,5-dihydrothienoyl3,2-quinolin-2- ditrifluoroacetate carboxamide -t--

MO o red heh

M

R xx and minor

Me (c) 2sSvson OTO

By a method similar to that of Example 349, the title compound was prepared from the compound of Auxiliary Example 94 and 3-(1H-imidazol-1-yl)upropan-1-amine.

РХ/МС 496 (М.Н).

Example 391

Preparation of M-(2-Bis(1-methylethyl)amino|ethyl)-5-methyl-3-(2-morpholin-4-ylethoxy)-4-oxo-4,5-dihydrothienoyl3,2-cquinoline-2-carboxamide ditrifluoroacetate

Me

Me- Me m- o 0/-4- Me i z s i mo

Me «s 2Svson Oto

By a method similar to that of Example 349, the title compound was prepared from the compound of Auxiliary Example 94 and M,M-bis(1-methylethyl)ethane-1,2-diamine.

РХ/МС 515 (М.Н).

Example 392

Preparation of 5-methyl-2-|((4-methylpiperazin-1-yl)ucarbonyl|-3-(2-morpholin-4-ylethoxy)thieno|3,2-syquinolin-4(5H)-one ditrifluoroacetate by 7 x

M M-Me x /

R same and mod

Me s 2sRson Oto

By a method similar to that of Example 349, the title compound was prepared from the compound of Auxiliary Example 94 and 1-methylpiperazine.

Example 393

Preparation of M, 5-dimethyl-M-(1-methylpyrrolidin-3-yl)-3-(2-morpholin-4-ylethoxy)-4-oxo-4,5-dihydrothienoyl3,2-quinoline-2-carboxamide ditrifluoroacetate

"Me

M c)

M. H

Z X Me s i

Mo

Me s 2gsvsoOn Oto

By a method similar to that of Example 349, the title compound was prepared from the compound of Auxiliary Example 94 and M,1-dimethylpyrrolidine-3-amine.

РХ/МС 485 (М.Н).

Example 394

Preparation of M-(2-(diethylamino)ethylide-M,B-dimethyl-3-(2-morpholin-4-ylethoxy)-4-oxo-4,5-dihydrothienoyl3,2-quinoline-2-carboxamide ditrifluoroacetate

IS!,

M-E at 00/-

M x Me

In and mok

Me s 2gsvSoNn oo

By a method similar to that of Example 349, the title compound was prepared from the compound of Auxiliary Example 94 and M,M-diethyl-M'-methylethane-1,2-diamine.

РХ/МС 501 (М--Н).

Example 395

Preparation of ditrifluoroacetate 5-methyl-3-(2-morpholin-4-ylethoxy)-2-((4-pyridin-2-ylpiperazin-1-yl)carbonyl|hyeno-3,2-sequinolin-4(5H)-one ) lu M-

M M with o

Mo

Me «s 2SEon To

By a method similar to that of Example 349, the title compound was prepared from the compound of Auxiliary Example 94 and 1-pyridin-2-ylpiperazine.

РХ/МС 534 (INN).

Example 396

Preparation of M, 5-dimethyl-4-oxo-3-(tetrahydrofuran-2-ylmethoxy)-4,5-dihydrothienoi33,2-c)quinoline-2-carboxamide (o) Me

M kh z (o) -

M (in)

Me

By a procedure similar to that of Example 300, the title compound was prepared from the compound of Auxiliary Example 95 and methanamine (2.0 M solution in THF).

РХ/МС 373 (INN).

Example 397

Preparation of M-butyl-5-methyl-4-oxo-3-(tetrahydrofuran-2-ylmethoxy)-4,5-dihydrothieno|3,2-si|quinoline-2-carboxamide

Me (c) ed

R and c) -

M c)

Me

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 95 and butan-1-amine.

РХ/МС 415 (М.Н).

Example 398

Preparation of M-(furan-2-ylmethyl)-5-methyl-4-oxo-3-(tetrahydrofuran-2-ylmethoxy)-4,5-dihydrothienoyl3,2-syquinoline-2-carboxamide

M (in,

R f (in, -y

M (in,

Me

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 95 and 1-furan-2-ylmethanamine.

РХ/МС 439 (INN).

Example 399

Preparation of 5-methyl-4-oxo-3-(tetrahydrofuran-2-ylmethoxy)-N-(tetrahydrofuran-2-ylmethyl)-4,5-dihydrothienoyl3,2-syquinoline-2-carboxamide

M)

WHAT ELSE F) -

M)

Me

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 95 and 1-(tetrahydrofuran-2-yl)methanamine.

РХ/МС 443 (М.Н).

Example 400

Preparation of 5-methyl-4-oxo-M-(2-phenylethyl)-3-(tetrahydrofuran-2-ylmethoxy)-4,5-dihydrothieno|3,2- syquinoline-2-carboxamide

M

R xx c) -

M c)

Me

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 95 and 2-phenylethanamine.

РХ/МС 463 (М--Н).

Example 401

Preparation of M-(2-methoxybenzyl)-5-methyl-4-oxo-3-(tetrahydrofuran-2-ylmethoxy)-4,5-dihydrothienoyl3,2-siquinoline-2-carboxamide by

M x Meo

Kk (in) -

M (in)

Me

By a method similar to the method given in Example 5, the title compound was obtained from the compound of Auxiliary Example 95 and 1-(2-methoxyphenyl)methanamine.

РХ/МС 479 (М.Н).

Example 402

Preparation of /5-methyl-4-oxo-3-(tetrahydrofuran-2-ylmethoxy)-M-(1,2,3,4-tetrahydronaphthalen-1-yl)-4,5-dihydrothieno|3,2-quinoline- 2-carboxamide

K

Y Z still

In (c) -

M c)

Me

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 95 and 1,2,3,4-tetrahydronaphthalene-1-amine.

РХ/МС 489 (М.Н).

Example 403

Preparation of M-(1,3-benzodioxol-5-ylmethyl)-5-methyl-4-oxo-3-(tetrahydrofuran-2-ylmethoxy)-4,5-dihydrothienoyl3,2-syquinolin-2-carboxamide - o (in ,

M

R

I 6) -y

M o)

Me

By a method similar to the method given in Example 5, the title compound was obtained from the compound of Auxiliary Example 95 and 1-(1,3-benzodioxol-5-ylumethanamine).

РХ/МС 493 (М.Н).

Example 404

Preparation of M, M-diethyl-5-methyl-4-oxo-3-(tetrahydrofuran-2-ylmethoxy)-4,5-dihydrothienoic3,2-syquinoline-2-carboxamide by

M x E xx ) -y

M)

Me

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 95 and M-ethylethanamine.

РХ/МС 415 (М.Н).

Example 405

Preparation of 5-methyl-2-(piperidin-1-ylcarbonyl)-3-(tetrahydrofuran-2-ylmethoxy)thieno|3,2-c)quinolin-4(5H)-one o, t,

R xh ) -y

M in,

Me

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 95 and piperidine.

РХ/МС 427 (MN).

Example 406

Preparation of M-(2-methoxyethyl)-M,B-dimethyl-4-oxo-3-(tetrahydrofuran-2-ylmethoxy)-4,5-dihydrothienoyl3,2-syquinoline-2-carboxamide

OMe at 00/-

M x Me xx F) -y

X F)

Me

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 95 and 2-methoxy-M-methylethanamine.

РХ/МС 461 (М--Н).

Example 407

Preparation of M-methoxy-M, 5-dimethyl-4-oxo-3-(tetrahydrofuran-2-ylmethoxy)-4,5-dihydrothienoi|3,2- syquinoline-2-carboxamide in) OMe

M

5 X Me s 6) -7

M o)

Me

By a procedure similar to that of Example 335, the title compound was prepared from the compound of Auxiliary Example 95 and M-methoxymethanamine hydrochloride.

РХ/МС 403 (М--Н).

Example 408

Preparation of 5-methyl-3-(tetrahydrofuran-2-ylmethoxy)-2-(thiomorpholin-4-ylcarbonyl)thieno|3,2-c)quinolin-4(5H)-one

M 5 ch

R xx o -

M o

Me

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 95 and thiomorpholine.

РХ/МС 445 (М.Н).

Example 409

Preparation of 2-(28)-2-(methoxymethyl)pyrrolidin-1-ylcarbonyl)-5-methyl-3-(tetrahydrofuran-2-ylmethoxy)thieno|3,2-c|quinolin-4(5H)-one

OMe o)

M

R

F o) -

M o)

Me

By a method similar to the method given in Example 5, the title compound was obtained from the compound of Auxiliary Example 95 and (2K)-2-(methoxymethyl)pyrrolidine.

РХ/МС 457 (М.Н).

Example 410

Preparation of M-benzyl-M, 5-dimethyl-4-oxo-3-(tetrahydrofuran-2-ylmethoxy)-4,5-dihydrothienoi|3,2- syquinoline-2-carboxamide h c.

M, x Me xx (c) -7

M (c)

Me

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 95 and M-methyl-1-phenylmethanamine.

РХ/МС 463 (М--Н).

Example 411

Preparation of 5-methyl-M, M-bis(2-methylpropyl)-4-oxo-3-(tetrahydrofuran-2-ylmethoxy)-4,5-dihydrothienoi3,2-syquinoline-2-carboxamide

Me

I have)

M Me

R;

Me s is) -

M is)

Me

By a method similar to that of Example 335, the title compound was prepared from the compound of Auxiliary Example 95 and 2-methyl-N-(2-methylpropyl)propan-1-amine hydrochloride.

РХ/МС 471 (М.Н).

Example 412

Preparation of trifluoroacetate M-I(III-«(dimethylamino)propyl|-5-methyl-4-oxo-3-(tetrahydrofuran-2-ylmethoxy)-4,5-dihydrothienoyl-3,2-siquinoline-2-carboxamide

Me '

Mo; Ed. Me

M

R c) -

M c)

Me se, soO, N

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 95 and M,M-dimethylpropane-1,3-diamine.

РХ/МС 444 (М.Н).

Example 413

Preparation of trifluoroacetate M-(2-(diethylamino)ethyl|-5-methyl-4-oxo-3-(tetrahydrofuran-2-ylmethoxy)-4,5-dihydrothienoyl-3,2-siquinoline-2-carboxamide

hey

M-EI at 0/-

She

R xx c) -y

M c)

Me sv,so,n

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 95 and M,M-diethylethane-1 2-diamine.

РХ/МС 458 (М.Н).

Example 414

Preparation of trifluoroacetate M-3-(1H-imidazol-1-yl)propyl|-5-methyl-4-oxo-3-(tetrahydrofuran-2-ylmethoxy)-4,5-dihydrothienoyl3,2-siquinoline-2-carboxamide

She

Chk o red he i

R s (in) -

M (in)

Me se, soO, N

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 95 and 3-(1H-imidazol-1-yl)upropan-1-amine.

РХ/МС 467 (М.Н).

Example 415

Preparation of trifluoroacetate M-2-I|bis(1-methylethyl)amino|ethyl)-5-methyl-4-oxo-3-(tetrahydrofuran-2-ylmethoxy)-4,5-dihydrothienoyl-3,2-siquinoline-2-carboxamide

Me

Me- Me m- o 0/-4- Me i

R c c) -y

M c)

Me svson

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 95 and M,M-bis(1-methylethyl)ethane-1,2-diamine.

РХ/МС 486 (М.Н).

Example 416

Preparation of 5-methyl-2-(4-methylpiperazin-1-yl)/carbonyl|-3-(tetrahydrofuran-2-ylmethoxy)thieno|3,2-syquinolin-4(5H)-one trifluoroacetate 6; / h

M M-Me x /

R xx ) -

X, )

Me seg, soON

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 95 and 1-methylpiperazine.

РХ/МС 442 (М.Н).

Example 417

Preparation of M, 5-dimethyl-M-(1-methylpyrrolidin-3-yl)-4-oxo-3-(tetrahydrofuran-2-ylmethoxy)-4,5-dihydrothienoyl3,2-siquinoline-2-carboxamide trifluoroacetate "Me

M

(in,

M

Z X Me s (in, -

M (in,

Me se, soN

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 95 and M, 1-dimethylpyrrolidine-3-amine.

РХ/МС 456 (М.Н).

Example 418

Preparation of /- M-(2-(diethylamino)ethyl|-M, 5-dimethyl-4-oxo-3-(tetrahydrofuran-2-ylmethoxy)-4,5-dihydrothienoyl3,2-quinoline-2-carboxamide trifluoroacetate

IS!,

M-E at 0/-

M

Z x Me xx (c) -

M (c)

Me se, soO, N

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 95 and M,M-diethyl-M'-methylethane-1,2-diamine.

РХ/МС 472 (М.Н).

Example 419

Preparation of 5-methyl-2-((4-pyridin-2-ylpiperazin-1-yl)ucarbonyl|-3-(tetrahydrofuran-2-ylmethoxy)thienoyl3,2-c|quinolin-4(5H)-one trifluoroacetate (F ) /ltu M-

M M in KhM / 7

And xx F) -y

M)

Me

SE.SO,N

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 95 and 1-pyridin-2-ylpiperazine.

РХ/МС 505 (М.Н).

Example 420

Preparation of 3-(2-ethoxyethoxy)-M, 5-dimethyl-4-oxo-4,5-dihydrothieno3,2-c|quinoline-2-carboxamide o Me

M

R s y

Mo OEi

Me

By a procedure similar to that of Example 300, the title compound was prepared from the compound of Auxiliary Example 96 and methanamine (2.0 M solution in THF).

РХ/МС 361 (М--Н).

Example 421

Preparation of M-butyl-3-(2-ethoxyethoxy)-5-methyl-4-oxo-4,5-dihydrothieno|3,2-c)quinoline-2-carboxamide

Me is) ed

M

Rs

M'o OEi:

Me

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 96 and butan-1-amine.

РХ/МС 403 (М--Н).

Example 422

Preparation of 3-(2-ethoxyethoxy)-M-(furan-2-ylmethyl)-5-methyl-4-oxo-4,5-dihydrothieno|3,2-c)quinoline-2-carboxamide

K-7

Mo

R s i

M'o OE!

Me

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 96 and 1-furan-2-ylmethanamine.

РХ/МС 427 (MN).

Example 423

Preparation of 3-(2-ethoxyethoxy)-5-methyl-4-oxo-M-(tetrahydrofuran-2-ylmethyl)-4,5-dihydrothieno|3,2-

sequinoline-2-carboxamide o th (c)

R xx y

M'o OEYI!

Me

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 96 and 1-(tetrahydrofuran-2-yl)methanamine.

РХ/МС 431 (М--Н).

Example 424

Preparation of 3-(2-ethoxyethoxy)-5-methyl-4-oxo-N-(2-phenylethyl)-4,5-dihydrothieno|3,2-c|quinoline-2-carboxamide

Yi g

K M

Mo OEY!

Me

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 96 and 2-phenylethanamine.

РХ/МС 451 (М--Н).

Example 425

Preparation of 3-(2-ethoxyethoxy)-N-(2-methoxybenzyl)-5-methyl-4-oxo-4,5-dihydrothienoyl3,2-c|quinoline-2-carboxamide o)

M x Nmeo xx i

M'To Oei:

Me

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 96 and 1-(2-methoxyphenyl)methanamine.

РХ/МС 467 (М.Н).

Example 426

Preparation of 3-(2-ethoxyethoxy)-5-methyl-4-oxo-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-4,5-dihydrothienoyl3,2-syquinoline-2-carboxamide h

Y Z

R

HU and

M'o OEYI!

Me

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 96 and 1,2,3,4-tetrahydronaphthalene-1-amine.

РХ/МС 477 (INN).

Example 427

Preparation of M-(1,3-benzodioxol-5-ylmethyl)-3-(2-ethoxyethoxy)-5-methyl-4-oxo-4,5-dihydrothienoi3,2-syquinoline-2-carboxamide - o) (F) »

R and S

M'o OE:

Me

By a method similar to the method given in Example 5, the title compound was obtained from the compound of Auxiliary Example 96 and 1-(1,3-benzodioxol-5-ylumethanamine).

РХ/МС 481 (М.Н).

Example 428

Preparation of 3-(2-ethoxyethoxy)-M,M-diethyl-5-methyl-4-oxo-4,5-dihydrothienoic|3,2-c|quinoline-2-carboxamide by

M

X Hey hu y

M' OEi

Me

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 96 and M-ethylethanamine.

РХ/МС 403 (INN).

Example 429

Preparation of 3-(2-ethoxyethoxy)-5-methyl-2-(piperidin-1-ylcarbonyl)thieno|3,2-c|quinolin-4(5H)-one

(at,

IN,

R zhu u

Mo Oeyi!

Me

By a method similar to that of Example 5, the title compound was prepared from the compound of Auxiliary Example 96 and piperidine.

РХ/МС 415 (М.Н).

Example 430

Preparation of 3-(2-ethoxyethoxy)-M-(2-methoxyethyl)-M,B-dimethyl-4-oxo-4,5-dihydrothienoic|3,2-syquinoline-2-carboxamide

OMe at 0/-

M

Х Me у хе) Oh!

Me

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 96 and 2-methoxy-M-methylethanamine.

РХ/МС 419 (М.Н).

Example 431

Preparation of /3-(2-ethoxyethoxy)-M-methoxy-M,5-dimethyl-4-oxo-4,5-dihydrothieno|3,2-c)quinoline-2-carboxamide

O / OMe

M

5 X Me same M

M'o OEi

Me

By a procedure similar to that of Example 335, the title compound was prepared from the compound of Auxiliary Example 96 and M-methoxymethanamine hydrochloride.

РХ/МС 391 (МН).

Example 432

Preparation of 3-(2-ethoxyethoxy)-5-methyl-2-(thiomorpholin-4-ylcarbonyl)thieno|3,2-c|quinolin-4(5H)-one

8) 7 x

M Z in x /

I am in

Mo OEi

Me

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 96 and thiomorpholine.

РХ/МС 433 (INN).

Example 433

Preparation of 3-(2-ethoxyethoxy)-2-(28)-2-(methoxymethyl)pyrrolidin-1-ylcarbonyl)-5-methylthienoi|3,2-syquinolin-4(5H)-one

OMe (in,

M

R

ХУ у

Mo Oi!

Me

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 96 and (2K)-2-(methoxymethyl)pyrrolidine.

РХ/МС 445 (М.Н).

Example 434

Preparation of M-benzyl-3-(2-ethoxyethoxy)-M,B-dimethyl-4-oxo-4,5-dihydrothienoi|Z,2-s|quinoline-2-carboxamide h p.

M x Me

HU M

M'o OE!

Me

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 96 and M-methyl-1-phenylmethanamine.

РХ/МС 451 (М.Н).

Example 435

Preparation of 3-(2-ethoxyethoxy)-5-methyl-M,M-bis(2-methylpropyl)-4-oxo-4,5-dihydrothienoi3,2-syquinoline-2-carboxamide

Me

me)

M Me

R; ho and Me

M'o OI

Me

By a method similar to that of Example 335, the title compound was prepared from the compound of Auxiliary Example 96 and 2-methyl-N-(2-methylpropyl)propan-1-amine hydrochloride.

РХ/МС 459 (М.Н).

Example 436

Preparation of M-III-"(dimethylamino)propyl|-3-(2-ethoxyethoxy)-5-methyl-4-oxo-4,5-dihydrothienoic|3,2-syquinoline-2-carboxamide trifluoroacetate

Me '

M o /-/ Me

M

R s ich

M' OEi

Me se, сОНн

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 96 and M,M-dimethylpropane-1,3-diamine.

РХ/МС 432 (М.Н).

Example 437

Preparation of trifluoroacetate M-(2-(diethylamino)ethyl|-3-(2-ethoxyethoxy)-5-methyl-4-oxo-4,5-dihydrothienoic-3,2-syquinoline-2-carboxamide

IS

M-EYI at 0/Й- th

R xx y

Mo OEi

Me se,so,n

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 96 and M,M-diethylethane-1 2-diamine.

РХ/МС 446 (М.Н).

Example 438

Preparation of /3-(2-ethoxyethoxy)-M-I(3-(1H-imidazol-1-yl)propyl|-5-methyl-4-oxo-4,5-dihydrothienoic|3,2-syquinolin-2 -carboxamide of trifluoroacetate -z

M o red ha

She

EE with i

Mo OE!

Me se,so,n

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 96 and 3-(1H-imidazol-1-yl)upropan-1-amine.

РХ/МС 455 (М.Н).

Example 439

Preparation of trifluoroacetate M-2-(bis(1-methylethyl)amino|ethyl)-3-(2-ethoxyethoxy)-5-methyl-4-oxo-4,5-dihydrothienoyl-3,2-siquinoline-2-carboxamide

Me

Me- Me - about 0/-4. I ate

R sh M heh) OE!

Me se, dream

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 96 and M,M-bis(1-methylethyl)ethane-1,2-diamine.

РХ/МС 474 (М.Н).

Example 440

Preparation of 3-(2-ethoxyethoxy)-5-methyl-2-((4-methylpiperazin-1-yl)carbonyligieno|3,2-c)quinolin-4(5H)-one trifluoroacetate 6; / h

M M-Me

With ШТ-

X xx and

M'o OEi

Me seg, dream

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 96 and 1-methylpiperazine.

РХ/МС 430 (INN).

Example 441

Preparation of trifluoroacetate 3-(2-ethoxyethoxy)-M, 5-dimethyl-M-(1-methylpyrrolidin-3-yl)-4-oxo-4,5-dihydrothieno|3,2-syquinoline-2-carboxamide -M

M e c)

M

Z x Me s i

M'so OE!

Me se, dream

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 96 and M, 1-dimethylpyrrolidine-3-amine.

РХ/МС 444 (М.Н).

Example 442

Preparation of M-(2-(diethylamino)ethyl|-3-(2-ethoxyethoxy)-M,5-dimethyl-4-oxo-4,5-dihydrothienoic|3,2-syquinoline-2-carboxamide trifluoroacetate

IS.,

M-EI at 0/-

M x Me hu i

M'o OEi

Me se, soN

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 96 and M,M-diethyl-M'-methylethane-1,2-diamine.

РХ/МС 460 (М.Н).

Example 443

Preparation of trifluoroacetate 3-(2-ethoxyethoxy)-5-methyl-2-((4-pyridin-2-ylpiperazin-1-yl/ucarbonylhieno|3,2-c)quinolin-4(5H)-one

O 0/;/- M-

М M s XM -/ s u

Mo OEi:

Me sen

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 96 and 1-pyridin-2-ylpiperazine.

РХ/МС 493 (INN).

Example 444

Preparation of 5-butyl-3-(2-ethoxyethoxy)-M-methyl-4-oxo-4-5-dihydrothienoi|3,2-s|quinoline-2-carboxamide (o,

Me

By a method similar to that of Example 300, the title compound was prepared from the compound of Auxiliary Example 104 and methanamine (2.0 M solution in THF).

РХ/МС 403 (INN).

Example 445

Preparation of M, 5-dibutyl-3-(2-ethoxyethoxy)-4-oxo-4,5-dihydrothienoic|3,2-c|quinoline-2-carboxamide

Me (F) ed

R s M / 6) OEI

Me

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 104 and butan-1-amine.

РХ/МС 445 (М.Н).

Example 446

Preparation of 5-butyl-3-(2-ethoxyethoxy)-M-(furan-2-ylmethyl)-4-oxo-4,5-dihydrothieno-3,2-c|quinoline-2-carboxamide (F) VK-

M d)

R

Sh. M

/ 6) OEI

Me

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 104 and 1-furan-2-ylmethanamine.

РХ/МС 469 (М--Н).

Example 447

Preparation of 5-butyl-3-(2-ethoxyethoxy)-4-oxo-N-(tetrahydrofuran-2-ylmethyl)-4,5-dihydrothienoyl3,2-syquinoline-2-carboxamide 9 2-3

M (c); more

In M

G o) OEi

Me

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 104 and 1-(tetrahydrofuran-2-yl)methanamine.

РХ/МС 473 (МН).

Example 448

Preparation of 5-butyl-3-(2-ethoxyethoxy)-4-oxo-M-(2-phenylethyl)-4,5-dihydrothieno|3,2-c|quinoline-2-carboxamide

Y U i g

In and / is, OEI

Me

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 104 and 2-phenylethanamine.

РХ/МС 493 (М.Н).

Example 449

Preparation of 5-butyl-3-(2-ethoxyethoxy)-N-(2-methoxybenzyl)-4-oxo-4,5-dihydrothienio3,2-c|quinoline-2-carboxamide

(in)

M x Nmeo y y / o OEi

Me

By a method similar to that of Example 5, the title compound was prepared from the compound of Auxiliary Example 104 and 1-(2-methoxyphenyl)methanamine.

РХ/МС 509 (МН).

Example 450

Preparation of 5-butyl-3-(2-ethoxyethoxy)-4-oxo-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-4,5-dihydrothienoyl3,2-syquinoline-2-carboxamide 5- 3

M

R

ХУ and / is); Hey

Me

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 104 and 1,2,3,4-tetrahydronaphthalene-1-amine.

РХ/МС 519 (М.Н).

Example 451

Preparation of M-(1,3-benzodioxol-5-ylmethyl)-5-butyl-3-(2-ethoxyethoxy)-4-oxo-4,5-dihydrothieno|3,2- syquinoline-2-carboxamide - o (in )

M

R

ХУ and / 8; Hey

Me

By a method similar to that of Example 5, the title compound was prepared from the compound of Auxiliary Example 104 and 1-(1,3-benzodioxol-5-yl)methanamine.

РХ/МС 523 (INN).

Example 452

Preparation of 5-butyl-3-(2-ethoxyethoxy)-M,M-diethyl-4-oxo-4,5-dihydrothieno|3,2-c|quinoline-2-

carboxamide c) A

M x KE with M

AND; and); Oh!

Me

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 104 and M-ethylethanamine.

РХ/МС 445 (М.Н).

Example 453

Preparation of 5-butyl-3-(2-ethoxyethoxy)-2-(piperidin-1-ylcarbonyl)thieno|3,2-c|quinolin-4(5H)-one c)

OV,

WITH

X and Y

G and); OEI

Me

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 104 and piperidine.

РХ/МС 457 (М.Н).

Example 454

Preparation of 5-butyl-3-(2-ethoxyethoxy)-M-(2-methoxyethyl)-M-methyl-4-oxo-4,5-dihydrothienoi3,2-syquinoline-2-carboxamide

OMe (o); ,-

M

5 x Me shck y / y); Hey

Me

By a method similar to the method given in Example 5, the title compound was obtained from the compound of Auxiliary Example 104 and 2-methoxy-M-methylethanamine.

РХ/МС 461 (М--Н).

Example 455

Preparation of 5-butyl-3-(2-ethoxyethoxy)-M-methoxy-M-methyl-4-oxo-4,5-dihydrothieno|3,2-c|quinoline-2-carboxamide

(6) OMe

M,

X Me and M / 6); ABOUT!

Me

By a method similar to that of Example 335, the title compound was prepared from the compound of Auxiliary Example 104 and M-methoxymethanamine hydrochloride.

РХ/МС 433 (М.Н).

Example 456

Preparation of 5-butyl-3-(2-ethoxyethoxy)-2-(thiomorpholin-4-ylcarbonyl)thieno|Y3,2-c)quinolin-4(5H)-one 8; 7 x

M. Z

What am I

AND; is); Hey

Me

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 104 and thiomorpholine.

РХ/МС 475 (М.Н).

Example 457

Preparation of 5-butyl-3-(2-ethoxyethoxy)-2-((28)-2-(methoxymethyl)pyrrolidin-1-ylcarbonyliluhienoi3,2-c)quinolin-4(5H)-one

Ohm c)

M

From x x x ich

AND; and); Oh!

Me

By a method similar to the method given in Example 5, the title compound was obtained from the compound of Auxiliary Example 104 and (2K)-2-(methoxymethyl)pyrrolidine.

РХ/МС 487 (М.Н).

Example 458

Preparation of M-benzyl-5-butyl-3-(2-ethoxyethoxy)-M-methyl-4-oxo-4,5-dihydrothieno|3,2-c|quinoline-2-carboxamide a,

M x Me shk and

AND; 8; OE

Me

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 104 and M-methyl-1-phenylmethanamine.

РХ/МС 493 (М.Н).

Example 459

Preparation of 5-butyl-3-(2-ethoxyethoxy)-M,M-bis(2-methylpropyl)-4-oxo-4,5-dihydrothieno|3,2- syquinoline-2-carboxamide

Me

Me 6)

M Me same and ho and Me 7 8; OE

Me

By a procedure similar to that of Example 335, the title compound was prepared from the compound of Auxiliary Example 104 and 2-methyl-N-(2-methylpropyl)/propan-1-amine hydrochloride.

РХ/МС 501 (М--Н).

Example 460

Preparation of 5-butyl-M-3-(dimethylamino)propyl|-3-(2-ethoxyethoxy)-4-oxo-4,5-dihydrothienoic|3,2-syquinoline-2-carboxamide trifluoroacetate

Me

M, (c); Ed. Me

M still with M 7 o) OEi

Me SE.SO,N

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 104 and M,M-dimethylpropane-1,3-diamine.

РХ/МС 474 (М.Н).

Example 461

Preparation of 5-butyl-M-(2-(diethylamino)ethyl|-3-(2-ethoxyethoxy)-4-oxo-4,5-dihydrothienoi3,2-

sequinoline-2-carboxamide trifluoroacetate

EE

M-EI (F), NYA-

M

R xx y 7 i); Hey

Me Se.SO,N

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 104 and M,M-diethylethane-1 2-diamine.

РХ/МС 488 (INN).

Example 462

Preparation of // 5-butyl-3-(2-ethoxyethoxy)-M-|3-(1H-imidazol-1-yl)propyl|-4-oxo-4,5-dihydrothienoi3,2-syquinoline-2-carboxamide trifluoroacetate 7 o red ha

M

R

HU and

M' OEi / SE.SO,N

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 104 and 3-(1H-imidazol-1-yl)upropan-1-amine.

РХ/МС 497 (MN).

Example 463

Preparation of trifluoroacetate M-2-(bis(1-methylethyl)aminoethyl)-5-butyl-3-(2-ethoxyethoxy)-4-oxo-4,5-dihydrothienoyl-3,2-siquinoline-2-carboxamide

Me me-- Me m- (F) No- Me

M

R s y

M' OEi / SE.SO,N

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 104 and M,M-bis(1-methylethyl)ethane-1,2-diamine.

РХ/МС 516 (М--Н).

Example 464

Preparation of trifluoroacetate 5-butyl-3-(2-ethoxyethoxy)-2-((4-methylpiperazin-1-yl)carbonyl|hyeno-3,2-c|quinolin-4(5H)-one

M M-Me their x /

X and M / o); Hey

Me SEZSO, N

By a method similar to the method given in Example 5, the title compound was obtained from the compound of Auxiliary Example 104 and 1-methylpiperazine.

РХ/МС 472 (М.Н).

Example 465

Preparation of 5-butyl-3-(2-ethoxyethoxy)-M-methyl-M-(1-methylpyrrolidin-3-yl)-4-oxo-4,5-dihydrothieno|3,2-c)quinoline-2-carboxamide trifluoroacetate m7Me 6)

M x Me s ich / 8); Hey

Me SeZSO, N

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 104 and M, 1-dimethylpyrrolidine-3-amine.

РХ/МС 486 (М.Н).

Example 466

Preparation of trifluoroacetate 5-butyl-N-(2-(diethylamino)ethyl|-3-(2-ethoxyethoxy)-N-methyl-4-oxo-4,5-dihydrothienoyl-3,2-siquinoline-2-carboxamide

EC

M-EI (o) H-

M

5 x Me same and / is); Oh!

Me SeZSO, N

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 104 and M,M-diethyl-M'-methylethane-1,2-diamine.

РХ/МС 502 (М.Н).

Example 467

Preparation of 5-butyl-3-(2-ethoxyethoxy)-2-K4-(pyridin-2-yl)piperazin-1-yl)ucarbonyligieno|3,2-syquinolin-4(5H)-one trifluoroacetate (c) lu M - in I

X s y 7 8; OE

Me SeSO, N

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 104 and 1-(pyridin-2-yl)piperazine.

РХ/МС 535 (М.Н).

Example 468

Preparation of 3-(2-ethoxyethoxy)-M-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno|3,2- syquinoline-2-carboxamide (6) Me

And with M

M'o OEi

WITH

By a procedure similar to that of Example 300, the title compound was prepared from the compound of Auxiliary Example 21 and methanamine (2.0 M solution in THF).

РХ/МС 465 (М--Н).

Example 469

Preparation of M-butyl-3-(2-ethoxyethoxy)-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoi3,2-syquinoline-2-carboxamide

Me (o) ed

M

R s y

M'o OE!

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 21 and butan-1-amine.

РХ/МС 507 (М.Н).

Example 470

Preparation of 3-(2-ethoxyethoxy)-N-(furan-2-ylmethyl)-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoyl3,2-syquinoline-2-carboxamide 9 I - th (c) also th

M'o OEi

WITH

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 21 and 1-furan-2-ylmethanamine.

РХ/МС 531 (М--Н).

Example 471

Preparation of //3-(2-ethoxyethoxy)-4-oxo-5-(2-oxo-2-phenylethyl)-N-(tetrahydrofuran-2-ylmethyl)-4,5-dihydrothienoyl3,2-syquinoline-2-carboxamide they are 8-7

M (c) same with i

M'To OEi

WITH

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 21 and 1-(tetrahydrofuran-2-yl)methanamine.

РХ/МС 535 (М.Н).

Example 472

Preparation of 3-(2-ethoxyethoxy)-4-oxo-5-(2-oxo-2-phenylethyl)-M-(2-phenylethyl)-4,5-dihydrothieno|3,2-syquinoline-2-carboxamide

M shkh and

M' OEi re

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 21 and 2-phenylethanamine.

РХ/МС 555 (М.Н).

Example 473

Preparation of 3-(2-ethoxyethoxy)-M-(2-methoxybenzyl)-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoyl3,2-siquinoline-2-carboxamide c)

M

X Nmeo s i

M'o OE! p

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 21 and 1-(2-methoxyphenyl)methanamine.

РХ/МС 571 (М--Н).

Example 474

Preparation of 3-(2-ethoxyethoxy)-4-oxo-5-(2-oxo-2-phenylethyl)-M-(1,2,3,4-tetrahydronaphthalen-1-yl)-4,5-dihydrothieno|3 ,2-quinoline-2-carboxamide 5

M still with M

M' OE

By a method similar to the method given in Example 5, the title compound was obtained from the compound of Auxiliary Example 21 and 1,2,3,4-tetrahydronaphthalene-1-amine.

РХ/МС 581 (МН).

Example 475

Preparation of /- M-(1,3-benzodioxol-5-ylmethyl)-3-(2-ethoxyethoxy)-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoi3,2-syquinoline -2-carboxamide - o (F)

M

R

HU and mo OEI ri

By a method similar to the method given in Example 5, the title compound was obtained from the compound of Auxiliary Example 21 and 1-(1,3-benzodioxol-5-ylumethanamine).

РХ/МС 585 (INN).

Example 476

Preparation of //3-(2-ethoxyethoxy)-M,M-diethyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoic3,2-syquinoline-2-carboxamide by

M

X Hey xx y

M' OEi ri

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 21 and M-ethylethanamine.

РХ/МС 507 (МН).

Example 477

Preparation of 3-(2-ethoxyethoxy)-5-(2-oxo-2-phenylethyl)-2-(piperidin-1-ylcarbonyl)thieno|3,2-c|quinolin-4(5H)-one

F)

TV,

R xx and

M'o OEi

WITH

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 21 and piperidine.

РХ/МС 519 (М.Н).

Example 478

Preparation of 3-(2-ethoxyethoxy)-M-(2-methoxyethyl)-M-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoyl-3,2-syquinoline-2-carboxamide

OMe (in); ,P-

M x Me s i

M' OE r:

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 21 and 2-methoxy-M-methylethanamine.

РХ/МС 523 (М.Н).

Example 479

Preparation of 3-(2-ethoxyethoxy)-M-methoxy-M-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoi3,2-syquinoline-2-carboxamide (F) OMe

M

5 X Me with S

M' OEi ri

By a procedure similar to that of Example 335, the title compound was prepared from the compound of Auxiliary Example 21 and M-methoxymethanamine hydrochloride.

РХ/МС 495 (М.Н).

Example 480

Preparation of 3-(2-ethoxyethoxy)-5-(2-oxo-2-phenylethyl)-2-(thiomorpholin-4-ylcarbonyl)thieno|3,2-c)quinolin-4(5H)-one by 7 x

M. Z

Z -W-

X shh and

M' OEII

WITH

By a method similar to the method given in Example 5, the title compound was obtained from the compound of Auxiliary Example 21 and thiomorpholine.

РХ/МС 537 (М.Н).

Example 481

Preparation of 3-(2-ethoxyethoxy)-2-((28)-2-(methoxymethyl)pyrrolidine-1-ylcarbonyl)-5-(2-oxo-2-phenylethyl)thienoyl3,2-c|quinoline-4(5H )-onu

OMe o)

M g s i

M' OE! r:

By a method similar to the method given in Example 5, the title compound was obtained from the compound of Auxiliary Example 21 and (2K)-2-(methoxymethyl)pyrrolidine.

РХ/МС 549 (М.Н).

Example 482

Preparation of M-benzyl-3-(2-ethoxyethoxy)-M-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoyl3,2-syquinoline-2-carboxamide

K.

M, x Me shkh i

M'o Oei r

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 21 and M-methyl-1-phenylmethanamine.

РХ/МС 555 (М.Н).

Example 483

Preparation of 3-(2-ethoxyethoxy)-M,M-bis(2-methylpropyl)-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoyl3,2-syquinoline-2-carboxamide

Me

Me

F)

M Me 8th -i ho ich Me

M' OEI h

By a method similar to that of Example 335, the title compound was prepared from the compound of Auxiliary Example 21 and 2-methyl-N-(2-methylpropyl)propan-1-amine hydrochloride.

РХ/МС 563 (М--Н).

Example 484

Preparation of M-I(III-«(dimethylamino)propyl|-3-(2-ethoxyethoxy)-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoIII3,2-c)quinoline- 2-carboxamide trifluoroacetate

Me

M o Me

Y g sh M

M' OEi (b)

SEZSO, N

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 21 and M,M-dimethylpropane-1,3-diamine.

РХ/МС 536 (М.Н).

Example 485

Preparation of 3-(2-ethoxyethoxy)-M-I(3-(1H-imidazol-1-yl)propyl|-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoyl3, 2-siIchinoline-2-carboxamide trifluoroacetate tk o red chem

M

R shkh i

M' OEi (c)

SEZSO, N

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 21 and 3-(1H-imidazol-1-yl)upropan-1-amine.

РХ/МС 559 (М.Н).

Example 486

Preparation of M-(2-Bis(1-methylethyl)amino|ethyl)-3-(2-ethoxyethoxy)-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno|III,2 -c|quinoline-2-carboxamide trifluoroacetate

Me

Me-X Me m- (F) ,i- Me i

R

J. M

M' OEi

WITH

SEZSO, N

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 21 and M,M-bis(1-methylethyl)ethane-1,2-diamine.

РХ/МС 578 (М.Н).

Example 487

Preparation of 3-(2-ethoxyethoxy)-2-((4-methylpiperazin-1-ylcarbonyl)-5-(2-oxo-2-phenylethyl)thienoyl3,2-syquinolin-4(5H)-one trifluoroacetate by 7 x

M M-Me

With -

H

HU M

M' OEi r:

SEZSO, N

By a method similar to the method given in Example 5, the title compound was obtained from the compound of Auxiliary Example 21 and 1-methylpiperazine.

РХ/МС 534 (М.Н).

Example 488

Preparation //3-(2-ethoxyethoxy)-M-methyl-M-(1-methylpyrrolidin-3-yl)-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno ,2-c|quinoline-2-carboxamide trifluoroacetate

- M

M e c)

M x Me s M

M' OEIIi c)

SEZSO, N

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 21 and M, 1-dimethylpyrrolidine-3-amine.

РХ/МС 548 (М.Н).

Example 489

Preparation of M-(2-(diethylamino)ethyl|-3-(2-ethoxyethoxy)-M-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoi3,2-siquinoline- 2-carboxamide trifluoroacetate

hey

M-EI (o, ,H-

M

5 x Mesh M

M' OEi o)

SE.SO,N

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 21 and M,M-diethyl-M'-methylethane-1,2-diamine.

РХ/МС 564 (М.Н).

Example 490

Preparation of 3-(2-ethoxyethoxy)-5-(2-oxo-2-phenylethyl)-2-(4-(pyridin-2-yl)piperazine-1-ylcarbonylilhieno|3,2-c)quinoline-4(5H )-one trifluoroacetate

(F) lu M-

M M s M / 7

X with M

M'o OEi

F)

SE, SO, N

By a method similar to that given in Example 5, the title compound was obtained from the compound of Auxiliary Example 21 and 1-(pyridin-2-yl)piperazine.

РХ/МС 597 (М.Н).

Example 491

Preparation of /- M-(2-amino-2-oxoethyl)-3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno|3,2- syquinoline-2-carboxamide

MN, and; 7 " and F)

R z OMe

M''o

H

To the solution of the compound of Auxiliary Example 7 (175 mg, 0.44 mmol), glycinamide (56 mg, 0.51 mmol),

To NOVI (89 mg, 0.66 mmol) and UUZSO (126 mg, 0.66 mmol) in DMF (5.0 mL) was added triethylamine (0.16 mL, 1.2 mmol) and the mixture was stirred at room temperature for 25 hours. Water was added to the reaction mixture and the precipitated solid was collected by filtration. The resulting solid was washed with water, ethanol, and diethyl ether, and recrystallized from DMF to give the title compound (124 mg, 54 95) as white crystals. "H-NMR (300 MHz, DMSO-av) 5: 3.95 (2H, d, 9U-5.3 Hz), 4.06 (ZH, s), 6.00 (2H, s), 7, 19 (1H, s), 7.30-7.40 (IN, m), 7.45-7.69 (5H, m), 7.73-7.82 (1H, m), 8.06 ( 1H, dd, 9U-7.9, 1.3 Gu), 8.13-8.22 (2H, m), 8.28 (1H, t, 9-5.3 Hz).

Example 492

Preparation of M-(2-(dimethylamino)ethyl|-3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoic|3,2-syquinoline-2-carboxamide

Me,

M-Me at 00/-

She

STILL with OMe

M (in) ;

By a procedure similar to that of Example 25, the title compound (124 mg, 81 95) was obtained as a white powder from the compound of Auxiliary Example 7 (130 mg, 0.33 mmol) and M,M-dimethylethylenediamine (44 mg , 0.49 mmol). "H-NMR (300 MHz, DMSO-α) 6: 2.23 (6H, s), 2.45 (2H, d, 9-6.2 Gu), 3.42 (2H, k, 9U-5 .9 Hz), 4.02 (ZH, s), 6.00 (2H, s), 7.35 (1TN, t, U-7.5 Hz), 7.48 (1IN, d, U-8 .7 Hz), 7.57 (1H, dd, 9U-7.2, 1.5 Gu), 7.64 (2H, t, uU-7.5

Hz), 7.76 (IN, t, 9-7.5 Hz), 8.05 (1H, dd, 9U-8.1, 1.5 Hz), 8.13-8.19 (ЗН, m ).

Example 493

Preparation of 3-methoxy-N-(2-(1-methylpyrrolidin-2-yl)ethyl|-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoyl-3,2-syquinolin-2- carboxamide

M, o Me i sh

In OMe

M (in) x

By a procedure similar to that of Example 25, the title compound (86 mg, 52 95) was obtained as a white powder from the compound of Auxiliary Example 7 (130 mg, 0.33 mmol) and 2-(2-aminoethyl)- 1-methylpyrrolidine (63 mg, 0.49 mmol). "H-NMR (300 MHz, DMSO-dv) 6: 1.45-1.70 (AN, m), 1.78-2.15 (AN, m), 2.23 (ZN, s), 2 .90-2.97 (1Н, m), 3.35-3.50 (2Н, m), 4.01 (ЗН, с), 5.99 (2Н, с), 7.35 (1ТН, t , 9U-7.5 Hz), 7.49 (1IN, d, U-8.1 Hz), 7.56 (1Н, dd, 9-7.2, 1.5 Gu), 7.60-7 .67 (2H, m), 7.77 (1H, t, U-7.5 Hz), 8.04 (1H, dd, 9U-7.8, 1.5 Hz), 8.16-8, 22 (ZN, m).

Example 494

Preparation of tert-butyl 2-(((3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno|3,2-c)quinoline-2-ylcarbonylamino)methylpiperidine-1 -carboxylate

Me o-«-Me o- Me

M a, i

R xx OMe

M (in) x

By a procedure similar to that of Example 25, the title compound (190 mg, 8595) was obtained as a white powder from the compound of Auxiliary Example 7 (150 mg, 0.38 mmol) and 2-aminomethyl-M-Bos-piperidine (122 mg, 0.57 mmol). "H-NMR (300 MHz, SOCI3) 6: 1.39 (9Н, s), 1.40-1.60 (1Н, m), 1.60-1.80 (5Н, m), 2.94 (1H, t, 9-12.6 Gu), 3.51-3.57 (1H, m), 3.70-3.90 (1TN, w), 4.03 (1H, d, 9U-14 .4 Hz), 4.15 (ZH, s), 4.45-4.60 (1H, m), 5.86 (2H, s), 7.01 (IN, d, U-8.4 Hz ), 7.26-7.28 (1H, m), 7.47 (1H, td, 9-81, 1.5 Hz), 7.59 (2H, t, 9-74 Gu), 7.65 -7.70 (2H, m), 7.90 (1H, dd, U-7.8, 1.2 Hu), 8.10-8.13 (2H, m).

Example 495

Preparation of M-(2-hydroxy-2-methylpropyl)-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrroloyi3,2-s |quinoline-2-carboxamide on "Me

Me N Me

In OMe

M (c); h

By a procedure similar to that of Example 25, the title compound (215 mg, 91 95) was obtained as a white powder from the compound of Auxiliary Example 28 (200 mg, 0.512 mmol) and 1-amino-2-methylpropane-2- beer (59.3 mg, 0.666 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.16 (6H, s), 3.29 (2H, d, 9-5.7 Hz), 4.02 (ZH, s), 4, 38 (ZH, s), 4.69 (1H, s), 5.98 (2H, s), 7.29-7.40 (2H, m), 7.46-7.51 (1H, m) , 7.64 (2H, t, U-7.4 Hz), 7.73-7.79 (1H, m), 8.03 (1H, t, 9-5.7 Hz), 8.16- 8.19 (2H, m), 8.39 (1TN, dd, 9U-8.3, 1.1 Hz).

Example 496

Preparation of /3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-N-(tetrahydrofuran-2-ylmethyl)-4,5-dihydro-1H-pyrrolyl3,2-s quinoline-2-carboxamide c)

Me. That's why

M' r

By a procedure similar to that of Example 25, the title compound (199 mg, 82 95) was obtained as a white powder from the compound of Auxiliary Example 28 (200 mg, 0.512 mmol) and 1-(tetrahydrofuran-2-yl)methanamine (68.7 μl, 0.666 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.56-1.67 (1H, m), 1.76-1.99 (ZH, m), 3.36-3.48 (2H, m), 3.63-3.71 (1Н, m), 3.79-3.86 (1Н, m), 3.96-4.04 (4Н, m), 4.36 (ЗН, с) , 5.97 (2H, s), 7.29-7.40 (2H, m), 7.45-7.51 (1H, m), 7.63 (2H, t, U9-7.5 Hz ), 7.73-7.79 (1H, m), 8.03 (1H, t, U-5.7 Hz), 8.16-8.19 (2H, m), 8.38 (1H, dd, u9-8.4, 1.2 Hz).

Example 497

Preparation of M-Itrans-2-hydroxycyclohexyl|-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5- dihydro-1H-pyrroloyi3,2-c|quinoline- 2-carboxamide o B, x z tOME

M'o ri

By a procedure similar to that of Example 25, the title compound (168 mg, 67 95) was obtained as a white powder from the compound of Auxiliary Example 28 (200 mg, 0.512 mmol) and trans-2-aminocyclohexanol hydrochloride (101 mg, 0.666 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.15-1.36 (4Н, m), 1.55-1.70 (2Н, m), 1.80-1.95 (1Н, m), 1.95-210 (1Н, m), 3.30-3.45 (1Н, m), 3.55-3.70 (1Н, m), 3.98 (ЗН, с), 4 .36 (ZN, s), 4.78 (1H, d, U-5.4 Hu), 5.97 (2H, s), 7.29- 7.39 (2H, m), 7.45- 7.50 (1TN, m), 7.63 (2Н, t, 9У-7.5 Hz), 7.73-7.79 (1Н, m), 7.87 (1Н, d, 9У-7, 5 Gu), 8.16-8.19 (2H, m), 8.38 (1H, dd, U-8.4, 1.2 Hz).

Example 498

Preparation of M-(1-(2-hydroxyethyl)piperidin-4-yl|-3-methoxy-4-oxo-5-(pyridin-2-ylmethyl)-4,5-dihydrothienoyl3,2-siquinoline-2-carboxamide dihydrochloride ed

M

M

5- Nancy hi toMe

Mmm, that's it

M

A mixture of the compound of Example 667 (60 mg, 0.15 mmol), 2-(chloromethyl)pyridine hydrochloride (37 mg, 0.22 mmol), potassium carbonate (52 mg, 0.37 mmol) and DMF (2 mL) was stirred at at room temperature for 3 hours and at 40 "C for 1 hour. The reaction mixture was diluted with a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with a saturated saline solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on amino silica gel ( eluate; ethyl acetate, ethyl acetate/methanol - from 50/1 to 50/2) to give a white solid. To a solution of the white solid in ethyl acetate (2 mL) was added a 4M solution of hydrochloride in ethyl acetate (0.1 mL), and the precipitate collected by filtration, washed with diethyl ether and dried under reduced pressure to give the title compound (4.2 mg, 5 95) as a white solid." H-NMR (300 MHz, DMSO-αv) 6:1 ,91-2.27 (AN, m), 3.05-3.30 (4Н, m), 3.60- 3.80 (AN, m), 4.07-4.10 (4H, m), 5.69 (2H, s), 7.28-7.34 (ZH, m), 7.41-7, 58 (2H, m), 7.77 (IN, t, U-8.6 Hz), 7.88 (1H, d, 9U-7.5 Hz), 8.02 (IN, d, U-8 ,1 Hu), 8.50 (1H, d, U-2.7 Hu), 9.40-9.55 (2H, w), 9.60-9.70 (1H, w).

Example 499

Preparation of 3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-M-(1-(3,3,3-trifluoro-2-hydroxypropyl)piperidin-4-yl|- 4,5-dihydro-1H-pyrrolo|3,2-c)quinoline-2-carboxamide one

WITH

E E

(in)

Me, her

MORE

KU OMe

M (in) x

By a procedure similar to that of Example 79, the title compound (150 mg, 64 95) was obtained as a white powder from the compound of Example 77 (200 mg, 0.400 mmol), 3-bromo-1,1,1-trifluoropropane -2-ol (62.2 μl, 0.600 mmol) and potassium carbonate (249 mg, 1.80 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.50-1.70 (2H, m), 1.80-1.95 (2H, m), 2.15-2.35 (2H, m), 2.45-2.60 (2Н, m), 2.75-2.90 (2Н, m), 3.75-3.90 (1Н, m), 3.98 (ЗН, с) , 4.05-4.20 (1Н, m), 4.31 (ЗН, с), 5.97 (2Н, с), 6.09-6.16 (IN, m), 7.28-7 .39 (2H, m), 7.45-7.50 (1H, m), 7.63 (2H, t, 9-7.7 Hz), 7.73-7.79 (1H, m), 7.90 (1H, d, 9U-8.1

Hz), 8.16-8.18 (2H, m), 8.37 (1H, dd, 9U-8.3, 1.4 Gu).

Example 500

Preparation of 3-methoxy-N-(2-(1-methylethyl)amino|ethyl)-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoyl3,2-siquinoline-2-carboxamide hydrochloride

But Me

M- ) ,-i- Me

M

That's her

M' r

To a solution of the compound of Example 97 (150 mg, 0.30 mmol) in ethyl acetate (10 mL) was added a 4M solution of hydrochloride in ethyl acetate (0.1 mL), and the resulting precipitate was collected by filtration, washed with ethyl acetate, and dried under reduced pressure to give the title compound (107 mg, 69 g) as a white powder. "H-NMR (300 MHz, DMSO-av) 5: 1.25 (6H, d, 9U-6.6 Hz), 3.13 (2H, w s), 3.30-3.45 (1H, m), 3.68 (2Н, k, 3-5.9 Hz), 4.07 (ЗН, с), 6.00 (2Н, с), 7.36 (1ТН, t, 9У-7.5 Hu), 7.50 (1H, d, U-8.4 Hz), 7.57-7.67 (ZH, m), 7.78 (IN, t, 9U-7.4 Hu), 8, 06 (1H, dd, U-7.8, 1.2 Hu), 8.18 (2H, d, U-8.4 Hu), 8.29 (1H, t, U-5.9 Hu), 8.77 (2H, w s).

Example 501

Preparation of M-(1-(2-hydroxyethyl)piperidin-4-yl|-3-methoxy-5-(4-methoxybenzyl)-1-methyl-4-oxo-4,5-dihydro-1H-pyrroloyi3,2- c|quinoline-2-carboxamide

ON

M

M

Me, N

H

"M tOME

Mm'

meo -

By a procedure similar to that of Example 79, the title compound (1.91 g, 75 95) was obtained as white crystals from the compound of Example 681 (2.50 g, 4.89 mmol). "H-NMR (300 MHz, DMSO-dv) 6: 1.58 (2H, k, 9U-9.9 Hz), 1.85 (2H, d, 9U-9.6 Hz), 2.18 ( 2H, t, U-9.9 Hz), 2.40 (2H, t, 9-63 Hz), 2.78 (2H, d, 9-11.4 Gu), 3.50 (2H, k, U-6.0 Hz), 3.69 (ZH, s), 3.70-3.85 (1H, w), 4.04 (ZH, s), 4.29 (ZH, s), 4, 35-4.40 (1H, m), 5.40-5.65 (2H, w), 6.86 (2H, d, 9-8.7 Hz), 7.14 (2H, d, U- 8.4 Gu), 7.24-7.30 (1H, m), 7.42-7.49 (2H, m), 7.91 (IN, d, 9U-7.8 Hz), 8, 33 (1H, d, 9U-8.1 Hz).

Example 502

Preparation of M-(1-hydroxycyclopropyl)methyl|-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrroloyi3,2-c|quinoline -2-carboxamide

HE oh oh

Me. M

M same tOME

Mm'o r

By a procedure similar to that of Example 25, the title compound (219 mg, 93 95) was obtained as a white powder from the compound of Auxiliary Example 28 (200 mg, 0.512 mmol) and 1-aminomethyl)cyclopropanol (58.0 mg, 0.666 mmol). "H-NMR (300 MHz, DMSO-av) 6: 0.55-0.65 (4H, m), 3.46 (2H, d, 9U-5.8 Hz), 4.01 (ZH, s ), 4.37 (ZH, s), 5.50 (1H, s), 5.97 (2H, s), 7.29-7.40 (2H, m), 7.45-7.51 ( 1H, m), 7.64 (2H, t, 9U-7.5 Hz), 7.73-7.79 (1H, m), 8.10 (1H, t, 9U-5.8 Hz), 8.16-8.19 (2H, m), 8.38 (1H, dd, 9U-8.1, 1.2 Hz).

Example 503

Preparation of M-((1-hydroxycyclohexyl)methyl|-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrroloyi3,2-s| quinoline-2-carboxamide on

F)

Me. Gu

LK zhi tome m'o r

By a procedure similar to that of Example 25, the title compound (235 mg, 92 95) was obtained as a white powder from the compound of Auxiliary Example 28 (200 mg, 0.512 mmol) and 1-aminomethyl)cyclohexanol (110 mg, 0.666 mmol). "H-NMR (300 MHz, DMSO-av) 5: 1.20-1.70 (TON, m), 3.25-3.40 (2H, m), 4.01 (ZH, s), 4 .38 (ZH, s), 4.50 (IN, s), 5.97 (2H, s), 7.29-7.40 (2H, m), 7.45-7.51 (1H, m ), 7.63 (2H, t, 9U-7.7 Hu), 7.73-7.79 (1H, m), 8.02 (IN, t, U-5.6 Hu), 8.16 -8.19 (2H, m), 8.38 (1H, dd, U-8,4,1,2 Hu).

Example 504

Preparation of 2-(12-(13-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno|3,2-c|quinolin-2-yl|carbonylmethyl)amino|ethylamino )-2-oxoethyl acetate

)

U-Me

N F)

M o ,.-410

M x Me hi tOME

Mo r

To a solution of the compound of Example 103 (150 mg, 0.31 mmol) and triethylamine (69 mg, 0.68 mmol) in THF (10 mL) was added acetoxyacetyl chloride (46 mg, 0.34 mmol) while cooling on ice. After stirring at room temperature for 1 hour, the reaction mixture was diluted with a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluate; ethyl acetate to ethyl acetate/methanol-50/1) to give a white solid. Crystallization of a white solid from ethyl acetate-hexane afforded the title compound (140 mg, 82 95) as white crystals. "H-NMR (300 MHz, SOS") 6: 2.28 (ZH, s), 3.19 (ZH, s), 3.62 (2H, w s), 3.77 (2H, w s) , 4.02 (ZH, s), 4.60 (2H, s), 5.87 (2H, s), 7.04 (1H, d, U-8.4 Hz), 7.20-7, 28 (1H, m), 7.45-7.50 (2H, m), 7.56 (2H, t, 9-7.5 Gu), 7.67 (IN, dd, 9U-7.5, 1.5 Hz), 7.84 (1H, dd, 9U-8.1, 1.2 Hz), 8.10-8.13 (2H, m).

Example 505

Preparation of 2-I4-(13-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrole|3,2- syquinoline-2-ylcarbonyl )iamino)piperidin-1-yl|-1,1-dimethyl-2-oxoethyl acetate

Me o o0-

In -MeO

M Me o)

M

Me. « N same tOME

M' r

By a procedure similar to that of Example 504, the title compound was obtained as a colorless oil from the compound of Example 77 (200 mg, 0.423 mmol) and 2-chloro-1,1-dimethyl-2-oxoethyl acetate (63.0 μl , 0.440 mmol). "H-NMR (300 MHz, DMSOO-av) 6: 1.36-1.50 (TON, m), 1.80-1.95 (2H, m), 2.07 (ZH, s), 2 .75-3.40 (2Н, m), 3.96 (ЗН, с), 4.00-4.25 (1Н, m), 4.29 (ЗН, с), 5.97 (2Н, с ), 7.29-7.39 (2H, m), 7.45-7.50 (1H, m), 7.63 (2H, t, 9U-7.5 Hz), 7.73-7, 79 (1H, m), 7.98 (1TN, d, U-7.8 Hu), 8.16-8.18 (2H, m), 8.37 (1H, dd, U-8.3, 1.1 Hz).

Example 506

Preparation of M-(1-(2-hydroxy-2-methylpropanoyl)piperidin-4-yl|-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5- dihydro-1H-pyrrolo|3,2-c)quinoline-2-carboxamide o On u -Me

M Me is)

Me. h

M same tOME

M' r

By a procedure similar to that of Example 508, the title compound (123 mg, 5595) was prepared as a white powder from the compound of Example 505, an 8M aqueous solution of sodium hydroxide (1.5 mL) and ethanol (12 mL). "H-NMR (300 MHz, DMSO-av) 6: 1.33 (6 N, s), 1.40-1.60 (2 N, m), 1.80-1.95 (2 N, m ), 2.75-3.45 (2 N, m), 3.97 (Z N, s), 4.00-4.20 (1 N, m), 4.31 (ZN, s), 4 ,20-4.80 (2N, m), 5.39 (1N, s), 5.97 (2N, s), 7.29-7.39 (2N, m), 7.45- 7.50 (1 N, m), 7.63 (2 N, t, 9U-7.5 Gsh), 7.73-7.79 (1 N, m), 7.93 (1 N, d, U-8.1 Gu), 8.15-8.18 (2 N, m), 8.37 (1 N, d, U-8.3, 1.4 Hz).

Example 507

Preparation of 3-methoxy-M-(2-(methoxyacetyl)amino|ethyl)-M-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno|3,2-siquinoline- 2-carboxamide

I'm not

OO ,-.F.110

M

X Me hi tOME

Mm' r

To a solution of the compound of Example 103 (100 mg, 0.21 mmol) and triethylamine (46 mg, 0.45 mmol) in THF (10 mL) was added methoxyacetyl chloride (25 mg, 0.23 mmol) while cooling on ice. After stirring at room temperature for 2 hours, the reaction mixture was diluted with a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluate; ethyl acetate to ethyl acetate/methanol-50/1) to give a white solid. Crystallization of a white solid from ethyl acetate-hexane afforded the title compound (61 mg, 56 g) as a white powder. "H-NMR (300 MHz, DMSO-av) is: 3.06 (ZH, s), 3.30-3.50 (5H, m), 3.50-3.65 (2H, w), 3 .70-3.95 (5H, m), 5.98 (2H, s), 7.34 (1H, t, U-7.4 Hz), 7.46-7.96 (7H, m), 8.18 (2H, d, 9-7.5 Gu).

Example 508

Preparation of M-2-(1-hydroxyacetyl)amino|ethyl)-3-methoxy-M-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno|3,2-quinoline-2 -carboxamide

M

9 /;/-. 0

M

Me

H

HU OMe

And MK is) re

A mixture of a solution of the compound of Example 504 (120 mg, 0.22 mmol) and a 4M aqueous solution of sodium hydroxide (2 ml) in THF (4 ml)-methanol (4 ml) was stirred at room temperature for 2 hours, the reaction mixture was diluted with a saturated aqueous solution of sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. Recrystallization of the crude solid from ethyl acetate-hexane afforded the title compound (65 mg, 58 95) as white crystals. "H-NMR (300 MHz, DMSO-α) 6: 3.06 (ZH, s), 3.20-3.40 (2H, m), 3.45-3.60 (2H, w), 3 ,70-3.86 (5H, m), 5.40-5.55 (1H, w), 5.98 (2H, s), 7.34 (1H, t, U-7.5 Gu), 7.47 (1H, d, U-8.4 Hz), 7.55 (1H, t, 9U-7.2 Hz), 7.64 (2H, t, 957.5 Hz), 7.77 ( 1H, t, 957.5 Hz), 7.87-7.96 (2H, m), 8.16-8.19 (2H, m).

Example 509

Preparation of 2-I4-(13-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno|3,2-c|quinolin-2-yl|carbonyl)amino)piperidin- 1-yl|-2-oxoethyl acetate (6) at 0-4

In Me

My

WITH

Х жх ОМе

Mo I

By a procedure similar to that of Example 123, the title compound (429 mg, 56 95) was obtained as a white solid from the compound of Example 105 (620 mg, 1.20 mmol). "H-NMR (300 MHz, SOS") 6: 1.44-1.64 (2Н, m), 2.01-2.28 (5Н, m), 2.88-3.05 (1Н, m ), 3.17-3.34 (1Н, m), 3.59-3.75 (1Н, m), 4.15 (ЗН, с), 4.19-4.35 (1Н, m), 4.41-4.54 (1H, m), 4.65-4.84 (2H, m), 5.87 (2H, s), 7.03 (IN, d, U-8.5 Gu) , 7.28-7.35 (1Н, m), 7.43-7.52 (1Н, m), 7.52-7.63 (ЗН, m), 7.65-7.74 (1Н, m), 7.91 (1H, dd, 97.9, 1.3 Hz), 8.06-8.18 (2H, m).

Example 510

Preparation of β-ethyl-M-(|1-(hydroxyacetyl)piperidin-4-yl|-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-3-propoxy-4,5- dihydro-1H-pyrrolo|3,2-s|Ipyridine-2-carboxamide o) OH

M

Me, and

MORE xx and

EI M (F) Me x

By a method similar to that given in Example 140, the title compound (199 mg, 74 95) was obtained as a white powder from the compound of Auxiliary Example 173 (198 mg, 0.50 mmol). "H-NMR (300 MHz, DMSO-α) 5: 0.92 (ZN, t, 9-7.4 Hz), 1.18 (ZN, t, 9-7.3 Hz), 1.26- 1.55 (2H, m), 1.59-1.75 (2H, m), 1.83-1.97 (2H, m), 2.57 (2H, k, 9U-7.4 Hz) , 2.77-2.91 (1Н, m), 3.01-3.18 (1Н, m), 3.60-3.75 (1Н, m), 3.89 (ЗН, с), 3 ,97-4.14 (ZH, m), 4.20-4.34 (ZH, m), 4.51 (1H, t, 9U-5.4 Hz), 5.59 (2H, s), 6.48 (1H, s), 7.56-7.68 (ZH, m), 7.69-7.78 (1H, m), 8.07-8.15 (2H, m).

Example 511

Preparation of M-P1-(hydroxyacetyl)piperidin-4-yl|-3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoyl3,2-syquinoline-2-carboxamide (6 ) ON

M

M

R xx OMe mo x

To a mixture of a solution of the compound of Example 509 (200 mg, 0.35 mmol) in THF (3.2 mL)-ethanol (11 mL) was added an 8M aqueous solution of sodium hydroxide (1.6 mL, 13 mmol) and the mixture was stirred at room temperature within 30 minutes. The reaction mixture was neutralized with 2M hydrochloric acid and extracted with a solvent mixture of ethyl acetate-THF. The extracts were combined, washed with saturated saline, dried over magnesium sulfate and filtered through amino silica gel.

The filtrate was concentrated under reduced pressure, the residue was recrystallized from THF-ethyl acetate to give the title compound (93 mg, 50 95) as a white solid. "H-NMR (300 MHz, SOSIz) 5: 1.43-1.64 (2H, m), 2.07-2.24 (2H, m), 2.98-3.24 (2H, m) , 3.44-3.58 (1H, m), 3.62 (IN, t, 9U-4.3 Hz), 4.15 (ЗН, s), 4.19 (2H, d, 9U-4 ,3 Hu), 4.22-4.35 (1Н, m), 4.44-4.57 (1Н, m), 5.86 (2Н,

c), 7.03 (1H, d, 9U-8.5 Gu), 7.28-7.34 (1H, m), 7.44-7.63 (4H, m), 7.64-7 .73 (1H, m), 7.91 (1H, dd, 9-7.8, 1.4

Hz), 8.06-8.16 (2H, m).

Example 512

Preparation of 2-42-(13-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno|3,2-c|quinolin-2-yl|carbonylamino)methyl|piperidin- 1-yl)-2-oxoethyl acetate (c)

U-me (in) 0-0.

Ma,

M

5-4. same thing

M' r

By a procedure similar to that of Example 123, the title compound was prepared as a colorless oil from the compound of Example 84 (500 mg, 0.95 mmol) and acetoxyacetyl chloride (142 mg, 1.04 mmol). "H-NMR (300 MHz, DMSO-α) 5: 1.10-1.80 (6Н, m), 2.00 (ЗН, s), 2.81 (0.5Н, t, 9-13, 1 Hz), 3.20-3.90 (ZN, m), 3.99-4.04 (3.5N, m), 4.24 (0.5N, d, 9U-10.5 Gu), 4.65 (0.5N, d, 9U-14.7 Gu), 4.80-4.82 (2N, m), 5.99 (2N, s), 7.35 (1N, t, U- 7.5 Hu), 7.49 (1H, d, U-8.7 Hu), 7.56-7.67 (ZH, m), 7.77 (1H, t, U-7.2 Hz) , 7.89 (0.5N, w t), 8.04 (1N, d, 9U-8.1 Gu), 8.17-8.19 (2N, m), 8.26 (0.5N, w c).

Example 513

Preparation of /-M-/1-(hydroxyacetyl)piperidin-2-yl|methyl)-3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno|3,2- syquinoline-2-carboxamide on o.

M nn,

M with tOME

I Shk c) ri

By a procedure similar to that of Example 508, the title compound (109 mg, 58 95) was obtained as a white powder from the compound of Example 512 (200 mg, 0.34 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.10-1.80 (6Н, m), 2.86 (0.5Н, t, 9-12.9 Gu), 3.26 (0 .5N, t, 9-15.0 Hz), 3.35-3.48 (1.5N, m), 3.70-3.90 (0.5N, m), 3.90-4.05 (4N, m), 4.05-4.15 (1.5N, m), 4.25-4.40 (1.5N, m), 4.75- 4.90 (0.5N, m) , 5.99 (2H, s), 7.35 (1H, t, U-7.5 Hz), 7.49 (1TN, d, U-8.4 Gu), 7.56-7.67 ( ЗН, m), 7.77 (1Н, t, 9У-7.5 Hz), 7.85-7.95 (0.5Н, w), 8.04 (1Н, dd, 9У-7.8, 1.2 Hz), 8.16-8.19 (2.5N, m).

Example 514

Preparation of 3-methoxy-N-(/1-(methoxyacetyl)piperidin-4-yl|-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo |3,2-s|quinoline-2-carboxamide

Oh Om

M what

M

Me. (N same toMe

Mm'o r

By a procedure similar to that of Example 507, the title compound was obtained (159 mg, 73 95) as a white powder from the compound of Example 77 (200 mg, 0.423 mmol) and methoxyacetyl chloride (40.3 μL, 0.440 mmol). "H-NMR (300 MHz, DMSO-α) 5: 1.35-1.65 (2 N, m), 1.80-2.00 (2 N, m), 2.80-2.95 ( 1 N, m), 3.05-3.25 (1

H, m), 3.30 (With H, s), 3.65-3.85 (1 N, m), 3.97 (With H, s), 4.00-4.25 (4 H, m), 4.31 (With N, s), 5.97 (2 N, s), 7.29-7.39 (2 N, m), 7.45-7.50 (1 N, m) , 7.63 (2 N, t, 9-7.7 Hz), 7.73-7.79 (1 N, m), 7.95 (1 N, d, 9U-8.1 Hz), 8 .15-8.18 (2 N, m), 8.37 (1 N, dd, 9U-8.3, 1.1 Hz).

Example 515

Preparation of M-(1-(ethylcarbamoyl)piperidin-4-yl|-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo| 3,2-s|quinoline-2-carboxamide)

IN-ME

Mm,

M

Me, s N «m tOMe mo r

To a mixture of the compound of Example 77 (200 mg, 0.423 mmol) and THF (10 mL) was added ethyl isocyanate (101 μL, 1.27 mmol) at 0 "C, and the mixture was stirred at room temperature for 15 hours.

The reaction mixture was diluted with ethyl acetate, washed with water and saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on amino silica gel (eluate; ethyl acetate). By recrystallization of the obtained solid from ethyl acetate-THF, the title compound (172 mg, 75 g) was obtained as a white powder. "H-NMR (300 MHz, DMSO-av) 6: 1.01 (ZH, t, 9U-7.1 Hu), 1.35-1.50 (2H, m), 1.75-1.90 (2H, m), 2.80-3.10 (AN, m), 3.80-3.95 (2H, m), 3.96 (ZH, s), 3.95-4.10 (1H , m), 4.30 (ZH, s), 5.97 (2H, s), 6.48 (1H, t, U-5.4 Hu), 7.28-7.39 (2H, m) , 7.44-7.50 (1H, m), 7.63 (2H, t, 9U-7.5 Gu), 7.73-7.79 (1H, m), 7.93 (1H, d , U-8.1 Hz), 8.15-8.18 (2H, m), 8.36 (1H, dd, 9U-8.3, 1.1 Hz).

Example 516

Preparation of 3-methoxy-1-methyl-N-(/1-(methylsulfonyl)piperidin-4-yl|-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo |3,2-s|quinoline-2-carboxamide o. Me mm o o MV,

Me. and

LK same tOME

M' r

To a mixture of the compound of Example 77 (200 mg, 0.423 mmol), triethylamine (423 μL, 3.18 mmol), and THF (10 mL) was added methanesulfonyl chloride (98.3 μL, 1.27 mmol) at 0 °C, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was diluted with ethyl acetate, washed with water and saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on amino silica gel (eluate; ethyl acetate). Recrystallization of the obtained solid from ethyl acetate gave the title compound (141 mg, 61 95) as a white powder." H-NMR (300 MHz, DMSO-α) 6: 1.60-1.75 (2H, m), 1.90-2.05 (2Н, m), 2.85-3.05 (5Н, m), 3.45-3.60 (2Н, m), 3.90-4.05 (1Н, m), 3.98 (ЗН , c), 4.30 (ZH, c), 5.97 (2H, c), 7.29-7.39 (2H, m), 7.45-7.50 (1H, m), 7, 63 (2H, t, U7.5 Hz), 7.73-7.79 (IN, m), 8.00 (1H, d, 9-7.8 Hz), 8.16-8.18 (2H , m), 8.37 (1H, dd, 9U-8.3, 1.1 Hz).

Example 517

Preparation of M-P1-(3-hydroxypropanoyl)piperidin-4-yl|-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo |3,2-s|quinoline-2-carboxamide at the Univ

M sh,

M

Me. in « N zhi tOME

Mm'o r

To a mixture of the compound of Example 77 (200 mg, 0.423 mmol), triethylamine (423 μL, 3.18 mmol), and THF (10 mL) was added p-propiolactone (39.9 μL, 0.635 mmol) at 0 °C, and the mixture was stirred at room temperature for 15 hours.The reaction mixture was diluted with ethyl acetate, washed with water and saturated saline, dried over magnesium sulfate and concentrated under reduced pressure.

The residue was purified by chromatography on amino silica gel (eluate; ethyl acetate). By recrystallization of the obtained solid from ethyl acetate, the title compound (70.0 mg, 30 95) was obtained as a white powder. "H-NMR (300 MHz, DMSO-α) 5: 1.30-1.60 (2 N, m), 1.80-2.00 (2 N, m), 2.45-2.55 ( 2 N, m), 2.80-2.90 (1

N, m), 3.15-3.25 (1 N, m), 3.61-3.70 (2 N, m), 3.80-3.95 (1 N, m), 3.97 (With H, s), 4.00-4.15 (1 N, m), 4.15-4.35 (1 N, m), 4.31 (ZH, s), 4.51 (1 N , t, U-5.4 Hz), 5.97 (2 N, s), 7.29-7.39 (2 N, m), 7.45-7.50 (1 N, m), 7.63 (2 H,

t, 7.5 Hz), 7.73-7.79 (1 N, m), 7.94 (1 N, d, 9U-7.8 Hz), 8.15-8.22 (2 N, m), 8.37 (1 N, dd, U-8.4, 1.2 Hz).

Example 518

Preparation // 3-methoxy-1-methyl-N-(1-(methylsulfonyl)acetyl|piperidin-4-yl)-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro- 1H-pyrrolo|3,2-c|quinoline-2-carboxamide

Me o. at 55 in /7o

M shO,

Me, M m- hmm tOME

M' ri

To a solution of the compound of Example 77 (200 mg, 0.423 mmol), (methylsulfonyl)acetic acid (76.0 mg, 0.550 mmol) and NOVI (85.8 mg, 0.635 mmol) in DMF (4 mL) was added UUZSO (122 mg, 0.635 mmol) while cooling on ice and the mixture was stirred at room temperature for 15 hours. The reaction mixture was diluted with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate.

The extracts were combined, washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on amino silica gel (eluate; ethyl acetate). By recrystallization of the obtained solid from ethyl acetate, the title compound (60.3 mg, 24 95) was obtained as white crystals. "H-NMR (300 MHz, DMSO-α) 6: 1.35-1.70 (2Н, m), 1.85-2.00 (2Н, m), 2.90-3.05 (1Н, m), 3.10 (ЗН, с), 3.20-3.35 (1Н, m), 3.90-4.20 (5Н, m), 4.20-4.35 (1Н, m) , 4.30 (ZH, s), 4.50 (2H, s), 5.97 (2H, s), 7.29-7.39 (2H, m), 7.45-7.50 (1H , m), 7.63 (2H, t, U-7.7 Hz), 7.73-7.79 (1H, m), 7.98 (1H, d, 9U-7.8 Hz), 8 ,16-8.18 (2H, m), 8.37 (1H, dd, U-8.3, 1.1 Gu).

Example 519

Preparation of 3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-M-(2-(2-oxopyrrolidin-1-yl)ethyl|-4,5-dihydro-1H- pyrroloY3,2-c|quinoline-2-carboxamide /in o /,-2, z0

Mke N

X xx OMe

M (in) x

By a procedure similar to that of Example 25, the title compound (153 mg, 60 95) was obtained as a pale yellow solid from the compound of Auxiliary Example 28 (200 mg, 0.51 mmol), 1-(2- aminoethyl)pyrrolidin-2-one (72 mg, 0.56 mmol), NOVI (89 mg, 0.66 mmol), MUZSO (127 mg, 0.66 mmol), and DMF (6.0 mL).

"H-NMR (300 MHz, SOS") 6: 1.97-2.14 (2H, m), 2.40 (2H, t, U-8.1 Hu), 3.44-3.59 ( 4H, m), 3.60-3.70 (2H,

M), 4.18 (ЗН, с), 4.47 (ЗН, с), 5.88 (2Н, с), 7.00-7.09 (1Н, m), 7.21-7.33 (1Н, m), 7.35-7.45 (1Н, m), 7.49-7.59 (2Н, m), 7.62-7.71 (1Н, m), 7.81 (1ТН , t, U-5.4 Hz), 8.07-8.16 (2H, m), 8.25 (1H, dd, 9U-8.3, 1.3 Hz).

Example 520

Preparation of 2--A-CIZ-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno|3,2-c|quinolin-2-yl|carbonylmethyl)amino|piperidin- 1-yl-2-oxoethyl acetate (c) is) 0-4 in Me

M

M x Me xx OMe

M (in) x

According to a method similar to the method given in Example 73, M-methyl-3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-M-piperidin-4-yl-4,5-dihydrothienoi|3 ,2-c)quinoline-2-carboxamide hydrochloride was obtained from the compound of Auxiliary Example 7 (500 mg, 1.3 mmol) and tert-butyl 4-(methylamino)piperidine-1-carboxylate (327 mg, 1.5 mmol), and then using the techniques given in

Examples 500 and 130 gave the title compound (182 mg, 24 95) as a white solid. "H-NMR (300 MHz, DMSO-α) 6: 1.59-1.91 (AN, m), 2.08 (ZH, s), 2.57-2.77 (1H, m), 2 .91 (ZN, s), 2.99-3.17 (IN, m), 3.32 (1Н, m), 3.69-3.90 (4Н, m), 4.29-4.50 (1H, m), 4.78 (2H, s), 5.98 (2H, s), 7.30-7.38 (1H, m), 7.43-7.70 (4H, m), 7.73-7.82 (1H, m), 7.97 (1H, dd, 9-7.9, 1.3 Hz), 8.11-8.22 (2H, m).

Example 521

Preparation of M-(/1-(hydroxyacetyl)piperidin-4-yl|-3-methoxy-M-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno|3,2 -syquinoline-2-carboxamide u

M

M x 5 x Me with OMe

Mo x

By a procedure similar to that of Example 511, the title compound (115 mg, 66 95) was obtained as a white solid from the compound of Auxiliary Example 520 (187 mg, 0.32 mmol), 8 M aqueous sodium hydroxide solution ( 1.6 ml), THF (3.2 ml) and ethanol (11 ml). "H-NMR (300 MHz, SOS") 6: 1.64-1.98 (4H, m), 2.67-2.89 (1H, m), 3.00 (ZH, s), 3, 05-3.19 (1Н, m), 3.52- 3.66 (2Н, m), 4.01 (ЗН, с), 4.10-4.26 (ЗН, m), 4.66- 4.85 (1H, m), 5.87 (2H, s), 7.04 (1H, d, U-8.5 Hz), 7.23-7.32 (1H, m), 7.42 -7.51 (1H, m), 7.52-7.62 (2H, m), 7.63-7.75 (1H, m), 7.84 (1H, dd, 9-7.9, 1.3 Hz), 7.99-8.20 (2H, m).

Example 522

Preparation of b-ethyl-M-|1-(hydroxyacetyl)piperidin-4-yl|-1-methyl-3-(1-methylethoxy)-4-oxo-5-(2-oxo-2-phenylethyl)-4, 5-dihydro-1H-pyrrolo|3,2-s|Ipyridine-2-carboxamide o on

M o MV,

Me. m Me

HU Fr

Me

EMO r

By a method similar to that given in Example 140, the title compound (237 mg, 88 95) was obtained as a colorless powder from the compound of Auxiliary Example 174 (188 mg, 0.50 mmol). "H-NMR (300 MHz, DMSO-α) 5: 1.12-1.26 (9Н, m), 1.26-1.57 (2Н, m), 1.84-1.97 (2Н, m), 2.57 (2H, k, 9-74 Hz), 2.76-2.94 (1H, m), 3.02-3.20 (1H, m), 3.59-3.76 (1H, m), 3.91 (ZN, s), 3.96-4.19 (ZN, m), 4.21-4.34 (IN, m), 4.50 (IN, t, U -5.5 Hu), 4.94-5.09 (1H, m), 5.59 (2H, s), 6.48 (1H, s), 7.56-7.69 (ZH, m) , 7.69-7.78 (IN, m), 8.06-8.16 (2H, m).

Example 523

Preparation of tert-butyl 3-(13-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo|3,2-c)quinoline- 2-ylcarbonyl)amino)pyrrolidine-1-carboxylate about Me

D Ieme

M'oh

F) Me

Me. M m-n zt OMe

Sea

By a method similar to that of Example 25, the title compound was obtained as a white powder from the compound of Auxiliary Example 28 (400 mg, 1.02 mmol) and tert-butyl 3-aminopyrrolidine-1-carboxylate (248 mg, 1 .33 mmol). "H-NMR (300 MHz, DMSO-α) 5: 1.41 (9 N, s), 1.87-2.02 (1 N, m), 2.05-2.19 (1 N, t , 9-14.7 Hz), 3.19-

3.46 (With H, m), 3.48-3.61 (1 H, m), 3.95 (With H, s), 4.30 (With H, s), 4.40-4, 52 (1 N, m), 5.97 (2 N, s), 7.27-7A1 (2 NN, m), 7.44-7.53 (1 N, m), 7.63 (2 N , t, U-7.6 Hu), 7.72-7.80 (1 N, m), 8.11-8.22 (Z H, m), 8.37 (1 N, dd, 9U- 8,3, 11 Gu.

Example 524

Preparation of tert-butyl I4-((3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo|3,2-c)quinoline -2-ylcarbonyl)amino)cyclohexylcarbamate

Me n o--Me

M- Me 0

With M

Me, Mr. OMe

Sea

By a procedure similar to that of Example 25, the title compound was obtained as a white powder from the compound of Auxiliary Example 28 (400 mg, 1.02 mmol) and tert-butyl (4-aminocyclohexyl)carbamate (285 mg, 1, 33 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.16-1.69 (1H, m), 1.72-1.96 (4H, m), 3.16-3.29 (1H, m), 3.65-3.80 (IN, t, 9U-11.1 Gu), 3.95 (2.5N, s), 4.07 (0.5N, s), 4.30 (2 .5N, s), 4.39 (0.5N, s), 5.97 (2N, s), 6.70-6.81 (0.8N, m), 6.85-6.94 (0 ,2Н, m), 7.25-7.42 (2Н, m), 7.43-7.53 (1Н, m), 7.58-7.68 (2Н, m), 7.72-7 .86 (2H, m), 8.14-8.22 (2H, m), 8.36 (1H, dd, U-8.3, 1.1 Hz).

Example 525

Preparation of M-(1-(hydroxyacetyl)pyrrolidin-3-yl|-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo| 3,2-s|quinoline-2-carboxamide o)

With M

Me, m-n same tOME

M'o re

A mixture of the compound of Example 523, ethyl acetate (2 ml) and a 4M solution of hydrochloride in ethyl acetate (2 ml) was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, a saturated aqueous sodium bicarbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extracts were combined, washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure, obtaining 3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-M-pyrrolidine-3 -yl-4,5-dihydro-1H-pyrrolo|3,2-c)quinoline-2-carboxamide (153 mg, 27 95) as a white powder.

To the mixture of 3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-M-pyrrolidine-

3-yl-4,5-dihydro-1H-pyrrole|3,2-c|quinoline-2-carboxamide (153 mg, 0.327 mmol), triethylamine (99.7 μL, 0.720 mmol) and THF (3 mL) were added acetoxyacetyl chloride (38.7 μL, 0.360 mmol) at 0 "C, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by by chromatography on amino silica gel (eluate; ethyl acetate). The resulting oil was dissolved in THF (4 mL) and ethanol (12 mL), 8M aqueous sodium hydroxide solution (1 mL) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture diluted with water, acidified TM with hydrochloric acid (8.p5 ml) and extracted with ethyl acetate. The extracts were combined, washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on amino silica gel (eluate; ethyl acetate/methanol - -10/0-9/1). By recrystallization of the obtained solid from ethyl acetate-THF, the title compound (121 mg, 72 g) was obtained as a white powder. "H-NMR (300 MHz, DMSO-α) 6: 1.86-2.31 (2H, m), 3.33-3.56 (ZH, m), 3.58-3.72 (1H, m), 3.94 (ZH, s), 4.02 (2H, dd, 9U-10.2, 5.7 Hz), 4.29 (ZH, d, 9-21 Hz), 4.40- 4.64 (2H, m), 5.97 (2H, s), 7.27-7.41 (2H, m), 7.43-7.52 (1H, m), 7.63 (2H, t, 927.6 Hz), 7.72-7.81 (1H, m), 8.12-8.23 (ZH, m), 8.37 (1H, d, 927.9 Gu).

Example 526

Preparation of M-(4-Khydroxyacetyl)amino|cyclohexyl)-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo|3,2 -c|quinoline-2-carboxamide "Shov

M g

With M

Me, m-n zt OMe

M'o re

To a mixture of the compound of Example 88 (190 mg, 0.363 mmol), triethylamine (151 μL, 1.09 mmol), and THF (7 mL) was added acetoxyacetyl chloride (46.9 μL, 0.436 mmol) at 0 °C, and the mixture was stirred at room temperature. temperature for 15 hours. The reaction mixture was diluted with ethyl acetate, washed with water and saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on amino silica gel (eluate; ethyl acetate). The resulting oil was dissolved in THF (2.5 ml ) and ethanol (5 ml), 8M aqueous sodium hydroxide solution (0.5 ml) was added and the mixture was stirred at room temperature for 1.5 hours.

The reaction mixture was diluted with water, acidified with 1M hydrochloric acid (4.5 ml) and extracted with ethyl acetate. The extracts were combined, washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on amino silica gel (eluate; ethyl acetate/"HF-10/0-0/10). By recrystallization of the obtained solid from ethyl acetate-THF, the title compound (91.1 mg, 46 95) was obtained as a white powder. "H-NMR (300 MHz, DMSO-dv) 6: 1.44 (AN, t, 9U-10.1 Hu), 1.67-1.85 (2Н, m), 1.88-2 .02 (2Н, m), 3.55-3.84 (АН, m), 3.96 (ЗН, с), 4.30 (ЗН, с), 5.43 (1Н, t, U-5 .8 Hz), 5.97 (2H, s), 7.23-7.40 (2H, m), 7.43-7.55 (2H, m), 7.63 (2H, t, 9- 7.6 Hz), 7.71-7.89 (2H, m), 8.11-8.23 (2H, m), 8.36 (1H, dd, uU-8.3, 1.1 Hz ).

Example 527

Preparation of M-(1-glycylpiperidin-4-yl)-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5- dihydro-1H-pyrrole|C3,2 -c) quinoline-2-carboxamide hydrochloride

oh my

M shO,

Me. hi

And hi tOME

Mo Nei ri

To a solution of the compound of Example 77 (250 mg, 0.529 mmol), M-Boc-glycine (111 mg, 0.635 mmol) and NOVI (107 mg, 0.794 mmol) in DMF (5 mL) was added M/U5CO (152 mg, 0.794 mmol ) while cooling on ice and the mixture was stirred at room temperature for 15 hours. The reaction mixture was diluted with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The extracts were combined, washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (2 ml), a 4M solution of hydrochloride in ethyl acetate (2 ml) was added and the mixture was stirred at room temperature for 1 hour.

The resulting solid was collected by filtration, washed with ethyl acetate (and recrystallized from ethanol-ethyl acetate to give the title compound (236 mg, 79 95) as white crystals. "H-NMR (300 MHz, DMSO-α) 6: 1.35 -1.70 (2Н, m), 1.85-2.00 (2Н, m), 2.95-3.10 (1Н, m), 3.15-3.30 (1Н, m), 3 .60-3.75 (1Н, m), 3.80-3.95 (2Н, m), 3.97 (ЗН, с), 4.05-4.30 (2Н, m), 4.31 (ZH, s), 5.97 (2H, s), 7.29-7.40 (2H, m), 7.45-7.51 (1H, m), 7.63 (2H, t, 9U -7.5 Hz), 7.73-7.79 (1H, m), 7.99 (1H, d, 9U-7.8 Hz), 8.08-8.21 (5H, m), 8 ,37 (1H, dd, U-8.3, 1.1 Gu).

Example 528

Preparation of 2-(2-(2-C(3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno|3,2-c)quinolin-2-yl|Icarbonyl )iamino)ethyl|pyrrolidin-1-yl)-2-oxoethyl acetate

I'm Yi

9 to-i i i) Me

WITH

Their

HU OMe

And M is)

WITH

By a procedure similar to that of Example 504, the title compound (200 mg, 89 95) was prepared as a white solid from the compound of Example 82 (200 mg, 0.38 mmol) and acetoxyacetyl chloride (57 mg, 0. 42 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.50-2.00 (6Н, m), 2.08 (ЗН, с), 2.90-3.10 (1Н, m), 3 ,38-3.49 (2Н, m), 3.50-3.65 (1Н, m), 4.05 (ЗН, с), 4.10-4.20 (1Н, m), 4.73 (2H, s), 5.99 (2H, s), 7.35 (1H, t, 9U-7.5 Hz), 7.49 (IN, d, 5U-8.4 Hz), 7.57 (1H, d, 9U-7.2 Gu), 7.64 (2H, t, 9U-7.5 Hz), 7.77 (1H, t, 9U-7.5 Hz), 8.04 (1H , d, 9U-7.8 Gu), 8.18 (2H, d, 9U-7.5 Hz), 8.45 (1TN, t, 9U-6.0 Hz).

Example 529

Preparation of 2-13-(13-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno|Y3,2-c|quinoline-2-

yl|carbonyl)iamino)methyl|pyrrolidin-1-yl-2-oxoethyl acetate

I am o) e

M

(in; K- 5

M

5-4 хи тОМе

Mm'o r

By a procedure similar to that of Example 504, the title compound (160 mg, 71 95) was prepared as a white solid from the compound of Example 669 (200 mg, 0.39 mmol) and acetoxyacetyl chloride (87 mg, 0. 86 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.60-1.78 (2H, m), 1.84-1.95 (1H, m), 2.07 (ZH, s), 2 .50-2.70 (1N, m), 3.07-3.57 (6N, m), 4.03 (1.5N, m), 4.04 (1.5N, s), 4.65 (2H, m), 6.00 (2H, s), 7.35 (1H, t, 9U-7.5 Hz), 7.49 (IN, d, U-8.4 Hz), 7.58 -7.67 (ZH, m), 7.77 (1H, t, U-7.5 Hz), 8.05 (1H, d, 9U-7.8 Hz), 8.16-8.23 ( 2H, m).

Example 530

Preparation of 2-CHgtrans-2-(|3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo|3,2-s) quinoline-2-ylcarbonyl)amino)cyclohexylamino)-2-oxoethyl acetate

Me. what

M H o ky toMe u-Me (c)

Mm' r

By a procedure similar to that of Example 504, the title compound (190 mg, 85 95) was prepared as a white solid from the compound of Example 85 (200 mg, 0.38 mmol) and acetoxyacetyl chloride (63 mg, 0. 46 mmol). "H-NMR (300 MHz, DMSO-av) 6: 1.20-1.41 (4H, m), 1.71 (2H, w s), 1.80-1.90 (1H, w d) , 2.04 (ЗН, с), 2.41-2.45 (1Н, m), 3.72-3.85 (2Н, m), 3.95 (ЗН, с), 4.26 (ЗН , s), 4.40 (2H, s), 5.97 (2H, s), 7.29-7.40 (2H, m), 7.48 (IN, t, 9U-7.8 Hz) , 7.64 (2H, t, 9U-7.5 Hu), 7.74-7.82 (2H, m), 7.95 (1H, d, 9U-8.1 Hu), 8.16- 8.19 (2H, m), 8.38 (1H, d, 9U-6.9 Hz).

Example 531

Preparation of 2-III-((3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrole|3,2- syquinoline-2- ylcarbonyl)iamino)azetidin-1-yl|-2-oxoethyl acetate

Me o 0o- x- IF)

M

93

Me, y

STILL with OMe

M (c); h

According to a method similar to the method given in Example 123, M-azetidin-3-yl-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H -pyrrolo|3,2-c|quinoline-2-carboxamide hydrochloride (600 mg) was obtained as a white powder from the compound of Auxiliary Example 670 (610 mg, 1.12 mmol). The title compound (121 mg, 17 95) was obtained as a white solid from the thus obtained white powder by a method similar to that described in

Examples 504. "H-NMR (300 MHz, DMSO-α) 6: 2.09 (ZH, s), 3.30-3.50 (2H, m), 3.86 (ZH, s), 4, 16 (1H, s), 4.36 (ZH, s), 4.40-4.42 (2H, m), 4.48 (2H, m), 5.97 (2H, s), 7.30 -7.40 (2H, m), 7.48 (1H, d, 9U-8.3 Hz), 7.64 (2H, t, 9-7.5

Hz), 7.76 (IN, t, 9-7.5 Hz), 8.16-8.23 (ЗН, m), 8.40 (1Н, d, 9У-7.5 Hz).

Example 532

Preparation of tert-butyl 3-((3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo|3,2-c|quinoline) -2-ylcarbonylamino)cyclohexylcarbamate

N

Mo); But

Me. M OO KhMe Mr. Me Me zhit OMe

Sea

By a procedure similar to that of Example 25, the title compound (395 mg, 66 95) was obtained as a white powder from the compound of Auxiliary Example 7 (400 mg, 1.02 mmol) and tert-butyl (33-aminocyclohexyl) carbamate (285 mg, 1.33 mmol). "H-NMR (300 MHz, DMSO-α) 6: 0.98-1.46 (1H, m), 1.65-1.90 (H, m), 2.00-2.12 (1H, m), 3.23-3.42 (IN, m), 3.73-3.88 (1H, m), 3.96 (2H, s), 4.04 (1H, s), 4.30 (2H, s), 4.35 (1H, s), 5.97 (2H, s), 6.76-6.94 (1H, m), 7.24-7.42 (2H, m), 7.43-7.53 (1H, m), 7.63 (2H, t, 9U-7.6 Gu), 7.71-7.80 (1H, m), 7.86 (1H, d, U-7.9 Hz), 8.12-8.22 (2H, m), 8.31-8.42 (1H, m).

Example 533

Preparation of N-(3-aminocyclohexyl)-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrroloyl-3,2-siquinoline-2- carboxamide hydrochloride

WITH

With M

Me, m-n same OMe mm'o NSI re

To a mixture of the compound of Example 532 (380 mg, 0.648) and ethyl acetate (4 ml) was added a 4M solution of hydrochloride in ethyl acetate (4 ml) and the mixture was stirred at room temperature for 2 hours.

The resulting solid was collected by filtration and washed with ethyl acetate to give the title compound (305 mg, 90 95) as a white powder. "H-NMR (300 MHz, DMSO-α) 6: 1.09-2.03 (7Н, m), 2.17-2.32 (1Н, m), 3.05-3.24 (1Н, m), 3.80-4.10 (4Н, m), 4.28 (2.5Н, s), 4.32 (0.5Н, s), 5.97 (2Н, s), 7.26 -7.53 (ZH, m), 7.63 (2H, t, 9U-7.4 Hz), 7.76 (1H, t, 9-74

Hz), 7.95-8.22 (6H, m), 8.37 (1H, d, U-8.3 Gu).

Example 534

Preparation of 2-1I3-((3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo|3,2-syquinoline-2- ilycarbonyl)iamino)cyclohexylamino)-2-oxoethyl acetate

N vd; about us- ЩюШЧДо

Me, M o Oo-

M ich N Me zh OMe

M'o re

By a procedure similar to that of Example 504, the title compound (223 mg, 70 95) was obtained as a white solid from the compound of Example 533 (285 mg, 0.546 mmol) and acetoxyacetyl chloride (70.4 μl, 0.655 mmol ). "H-NMR (300 MHz, DMSO-α) 5: 1.06-1.48 (AN, m), 1.67-1.93 (ZH, m), 2.00-2.12 (4Н, m), 3.59-3.76 (1Н, m), 3.78-3.91 (1Н, m), 3.95 (2.7Н, s), 4.03 (0,ЗН, s) , 4.29 (2.7 N, s), 4.35 (0,ZH, s), 4.41 (1.8N, s), 4.45 (02N, s), 5.97 (2N, c), 7.26-7.40 (2H, m), 7.43-7.52 (1H, m), 7.63 (2H, t, 9U-7.6 Gu), 7.72-7 .80 (1H, m), 7.85-7.99 (2H, m), 8.11-8.23 (2H, m), 8.36 (1H, dd, 9U-8.4.1, 2 Hz).

Example 535

Preparation of M-(3-Khydroxyacetyl)amino|cyclohexyl)-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo|3,2 -c|quinoline-2-carboxamide

No:

With M (c)

Me, he m-n j t OMe

M'o re

By a procedure similar to that of Example 508, the title compound (173 mg, 93 90) was obtained as a white powder from the compound of Example 534 (200 mg, 0.34 mmol), 8M aqueous sodium hydroxide solution (0.5 ml), THF (2.5 ml) and ethanol (5 ml). "H-NMR (300 MHz, DMSO-α) 6: 1.12-1.50 (AN, m), 1.66-1.82 (2Н, m), 1.84-1.94 (1Н, m), 1.98-2.10 (1N, m), 3.65-3.91 (AN, m), 3.95 (2.7N, s), 4.06 (0, ЗН, s) , 4.30 (2.7N, s), 4.35 (0.3N, s), 5.39 (1N, d, 9-51 Hu), 5.98 (2N, s), 7.24- 7.А1 (2Н, m), 7.46 (1Н, d, U-7.8 Gu), 7.54-7.69 (ЗН, m), 7.76 (1ТН, t, U -.3 Hz), 7.87 (1H, d, 9U-7.9 Hz), 8.17 (2H, d, 9-7.7 Hz), 8.37 (IN, d, U-8.3 Hz) .

Example 536

Preparation of methyl trans-4-(3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo|3,2-c)quinoline- 2-ylcarbonyl)amino)cyclohexanecarboxylate is)

In Sh

About Z

Me, M m-n zhit OMe

M'o re

By a procedure similar to that of Example 25, the title compound (535 mg, 79 95) was obtained as a white powder from the compound of Auxiliary Example 7 (500 mg, 1.28 mmol), triethylamine (230 μl, 1.66 mmol) and methyl trans-4-aminocyclohexanecarboxylate hydrochloride (321 mg, 1.66 mmol). "H-NMR (300 MHz, DMSO-dv) 6: 1.27-1.60 (AN, m), 1.87-2.07 (AN, m), 2.25-2.41 (1Н, m), 3.60 (ZN, s),

3.69-3.86 (1H, m), 3.96 (ZH, s), 4.30 (ZH, s), 5.96 (2H, s), 7.25-7.41 (2H, m), 7.43-7.53 (1H, m), 7.63 (2H, t, 9U-7.6 Hz), 7.71-7.88 (2H, m), 8.11-8 ,23 (2H, m), 8.36 (1H, dd, U-8,3,1,1 Gu).

Example 537

Preparation of trans-4-(|3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo|3,2- sequinoline-2- ilycarbonyl)iamino)cyclohexanecarboxylic acid

F)

I

F) M

Me, m-n same tOME

M'o re

A mixture of the compound of Example 536 (300 mg, 0.566 mmol), 8M aqueous sodium hydroxide solution (1 ml) and ethanol (7 ml) was stirred at room temperature for 2 hours. The reaction mixture was acidified with EM hydrochloric acid (1.5 mL) and the precipitated solid was collected by filtration. The resulting solid was washed with water and dried under reduced pressure to give the title compound (225 mg, 81 95) as a white powder. "H-NMR (300 MHz, DMSO-α) 6: 1.25-1.57 (AN, m), 1.85-2.05 (4Н, m), 2.10-2.26 (1Н, m), 3.67-3.85 (1Н, m), 3.98 (ЗН, с), 4.29 (ЗН, с), 5.97 (2Н, с), 7.25-7.А41 (2H, m), 7.42-7.52 (1H, m), 7.63 (2H, t, U-7.6 Hz), 7.71-7.88 (2H, m), 8, 12-8.24 (2H, m), 8.37 (1H, dd, U-8.3, 1.1 Hz), 12.23 (IN, w s).

Example 538

Preparation of M-(trans-4-(2-hydroxyethyl)carbamoyl|cyclohexyl)-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1 H -pyrrolo|3,2-s|quinoline-2-carboxamide on o,-

M

In I

6, ch

M o N j tOME

M'o re

To a solution of the compound of Example 537 (215 mg, 0.417 mmol), 2-aminoethanol (32.5 μl, 0.542 mmol) and

NOVI (84.6 mg, 0.626 mmol) in DMF (5 mL) was added UUZSO (120 mg, 0.626 mmol) while cooling on ice and the mixture was stirred at room temperature for 15 h. The reaction mixture was diluted with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate.

The extracts were combined, washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on amino silica gel (eluate; ethyl acetate/methanol--10/0-8/2). By recrystallization of the obtained solid from ethyl acetate-THF, the title compound (131 mg, 56 95) was obtained as a white powder. "H-NMR (300 MHz, DMSO-α) 5: 1.22-1.58 (AN, m), 1.71-1.86 (2H, m), 1.90-2.03 (2H, m), 2.05-2.20 (1Н, m), 3.03-3.18 (2Н, m), 3.34-3.44 (2Н, m), 3.65-3.84 ( 1Н, m), 3.98 (ЗН, с), 4.30 (ЗН, с), 4.63 (1ТН, т, У-5.6 Hu), 5.97 (2Н, с), 7, 25-7.41 (2H, m), 7.47 (1H, t, U-7.7 Hu), 7.58-7.68 (2H, m), 7.70-7.88 (ZH, m), 8.17 (2H, d, uU-7.6 Hz), 8.37 (1H, d, 9-81 Hz).

Example 539

Preparation of 2-III-((3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrole|3,2- syquinoline-2- ylcarbonyl)amino)piperidine-1-yl|-2-oxoethylacetate (F)

Me, M H- Me m o xx OMe

Mo;

By a procedure similar to that of Example 25, the title compound (284 mg, 39 95) was obtained as a white solid from the compound of Auxiliary Example 28 (500 mg, 1.3 mmol), tert-butyl 3-aminopiperidine -1-carboxylate (257 mg, 1.3 mmol), NOVI (203 mg, 1.5 mmol), MUZSO (294 mg, 1.5 mmol), DMF (15 ml), a 4M solution of hydrochloride in ethyl acetate (4, 0 mL), THF (4.0 mL), methanol (4.0 mL), acetoxyacetyl chloride (0.098 mL, 0.91 mmol), triethylamine (0.28 mL, 2.0 mmol), and THF (16 mL). "H-NMR (300 MHz, SOSIzv) 6: 1.64-1.88 (ZH, m), 1.93-2.09 (1H, m), 2.16 (ZH, s), 3.24 -3.59 (2H, m), 3.67- 3.82 (2H, m), 4.04-4.24 (AN, m), 4.47 (ZN, s), 4.67-4 .88 (2H, m), 5.79-5.97 (2H, m), 7.05 (1H, d, 9U-7.9 Gu), 7.20-7.34 (1H, m), 7.37-7.46 (1H, m), 7.55 (2H, t, 9U-7.6 Hz), 7.61-7.71 (1H, m), 7.82 (1H, d, 9U-7.0 Gu), 8.07-8.16 (2H, m), 8.26 (1H, dd, 9U-8.2, 1.4 Hz).

Example 540

Preparation of tert-butyl 4-(13-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo|3,2-c)quinoline- 2-ylcarbonyl)iamino)methyl|piperidine-1-carboxylate (6)

We are in

Me. M (F) kMe

M. e

X xx OMe

Mo

H

By a procedure similar to that of Example 25, the title compound (521 mg, 69 95) was obtained as a white solid from the compound of Auxiliary Example 28 (500 mg, 1.3 mmol), tert-butyl 4-( aminomethyl)piperidine-1-carboxylate (302 mg, 1.4 mmol), NOVI (208 mg, 1.5 mmol), UUZS (294 mg, 1.5 mmol) and DMF (15 ml). "H-NMR (300 MHz, SOSIz) 5: 1.14-1.33 (2H, m), 1.41-1.51 (9H, m), 1.70-1.85 (ZH, m) , 2.63-2.80 (2H, m), 3.37 (2H, t, 9-61 Hz), 4.03-4.25 (5H, m), 4.47 (ЗН, s), 5.89 (2H, s), 7.05 (1H, d, 9U-8.5 Hz), 7.21-7.31 (1H, m), 7.36-7.46 (1H, m) , 7.50-7.60 (2H, m), 7.62-7.70 (1H, m), 7.76 (1H, t, 9U-5.9 Gu), 8.05-8.16 (2H, m), 8.26 (IN, dd, U-8.3, 1.3 Hz).

Example 541

Preparation of tert-butyl 4-C3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo|3,2-c)quinoline-2 -ilycarbonylUumethyl)amino|Ipiperidine-1-carboxylate

)

Uh-oh

M Zh-Me

Me Me)

Me, M,

M x Me xx OMe mo x

By a procedure similar to that of Example 25, the title compound (565 mg, 75 90) was obtained as a white solid from the compound of Auxiliary Example 28 (500 mg, 1.3 mmol), tert-butyl 4-( methylamino)piperidine-1-carboxylate (274 mg, 1.3 mmol), NOVI (208 mg, 1.5 mmol), MUBSO (294 mg, 1.5 mmol) and DMF (15 mL). "H-NMR (300 MHz, SOS") 5: 1.42-1.52 (9H, m), 1.65-1.86 (4H, m), 2.56-2.97 (2H, m), 3.03 (ЗН, с), 3.97-4.20 (7Н, m), 4.22-4.37 (1Н, m), 4.61-4.81 (1Н, m) , 5.89 (2H, s), 7.05 (1H, d, 9U-8.5 Hz), 7.19-7.30 (1H, m), 7.33-7.43 (1H, m ), 7.49-7.59 (2H, m), 7.60-7.70 (1H, m), 8.05-8.15 (2H, m), 8.18 (1H, d, U -7.4 Hz).

Example 542

Preparation of 3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-M-(piperidin-4-ylmethyl)-4,5-dihydro-1H-pyrroloyl3,2-siIquinoline-2 -carboxamide hydrochloride

Me, »

M

Х шхх ОМе мМ зх

A mixture of a solution of the compound of Example 540 (500 mg, 0.85 mmol) and a 4M solution of the hydrochloride in ethyl acetate (4.0 mL) in THF (4.0 mL)-methanol (4.0 mL) was stirred at room temperature for 2 hours.

A 4M solution of hydrochloride in ethyl acetate (4.0 mL) and methanol (8.0 mL) were added, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure and recrystallized from methanol-diethyl ether to give the title compound (356 mg, 80 95) as a pale yellow solid. "H-NMR (300 MHz, DMSO-α) 5: 1.29-1.48 (2H, m), 1.75-1.95 (ZH, m), 2.78-2.94 (2H, m), 3.18-3.38 (4Н, m), 4.00 (ЗН, с), 4.31 (ЗН, с), 5.98 (2Н, с), 7.27-7.42 (2H, m), 7.44-7.53 (1H, m), 7.59-7.69 (2H, m), 7.72-7.81 (IN, m), 8.07-8 .22 (ZH, m), 8.38 (1H, dd, 9U-8.4, 1.2 Hz), 8.51 (2H, w s).

Example 543

Preparation of M-/1-(hydroxyacetyl)piperidin-3-yl|-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo| 3,2-s|quinoline-2-carboxamide

(c) that o) he

Me, uh

MORE SHHH OMe mo x

By a procedure similar to that of Example 511, the title compound (69 mg, 43 95) was obtained as a white solid from the compound of Example 539 (174 mg, 0.30 mmol), 8M aqueous sodium hydroxide solution (1 .6 ml), THF (3.2 ml) and ethanol (11 ml). "H-NMR (300 MHz, DMSO-α) 6: 1.44-1.81 (ЗН, m), 1.84-1.96 (1Н, m), 3.29-3.61 (ЗН, m), 3.80-3.90 (1Н, m), 3.91-4.02 (АН, m), 4.04-4.17 (2Н, m), 4.35 (ЗН, с) , 4.54 (1H, t, 9U-5.4 Hz), 5.97 (2H, s), 7.27-7.42 (2H, m), 7.44-7.53 (1H, m ), 7.59-7.69 (2H, m), 7.71-7.81 (1H, m), 7.89-8.01 (1H, m), 8.12-8.21 (2H , m), 8.38 (1H, dd, 3-8,3,11 Gu).

Example 544

Preparation of 2--A-IDCZ-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo|3,2-si|quinoline-2 -ylcarbonyl)amino)methyl|piperidin-1-yl)-2-oxoethyl acetate (c); le

Me, M o

M N H-Me

Oh my God

M (c); h

To a solution of the compound of Example 542 (400 mg, 0.76 mmol) and triethylamine (0.29 mL, 2.1 mmol) in THF (17 mL) was added acetoxyacetyl chloride (0.10 mL, 0.95 mmol) while cooling on ice and the mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The extracts were combined, washed with saturated saline, dried over magnesium sulfate and filtered through amino silica gel. The filtrate was concentrated and the residue was recrystallized from ethanol-hexane to give the title compound (321 mg, 71 95) as a white solid. "H-NMR (300 MHz, SOSIzv) 6: 1.16-1.37 (2H, m), 1.78-1.99 (ZH, m), 2.18 (ZH, s), 2.58 -2.71 (1Н, m), 2.99- 3.15 (1Н, m), 3.31-3.43 (2Н, m), 3.63-3.76 (1Н, m), 4 ,17 (ZH, s), 4.47 (ZH, s), 4.57-4.66 (1H, m), 4.73 (2H, s), 5.89 (2H, s), 7, 01-7.08 (1N, m), 7.20-7.33 (1TN, m), 7.37-7.47 (1N, m), 7.50-7.60 (2N, m), 7.62-7.71 (1H, m), 1.19 (1H, t, uU-5.9 Hz), 8.07-8.17 (2H, m), 8.26 (1H, dd, 9U-8.3, 1.3 Hz).

Example 545

Preparation of 2--A-CYZ-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo|3,2- syquinoline-2-ylcarbonylleumethyl )amino|piperidin-1-yl)-2-oxoethyl acetate

(c) at 0-4

M sh,

Me, M,

M x Me xx OMe

Mo x

By a procedure similar to that of Example 123, the title compound (226 mg, 40 95) was obtained as a white solid from the compound of Example 541 (565 mg, 0.96 mmol), a 4 M solution of hydrochloride in ethyl acetate (4 .0 mL), THF (4.0 mL), methanol (4.0 mL), acetoxyacetyl chloride (0.077 mL, 0.71 mmol), triethylamine (0.22 mL, 1.6 mmol), and THF (13 mL) . "H-NMR (300 MHz, SOS") 8: 1.70-1.97 (AN, m), 2.15-2.24 (ZH, m), 2.50-2.83 (1H, m ), 3.03 (ЗН, с), 3.10- 3.33 (1Н, m), 3.63-3.86 (1Н, m), 4.02 (ЗН, с), 4.04- 4.11 (ZN, m), 4.60-4.87 (AN, m), 5.89 (2H, s), 7.02-710 (IN, m), 7.17-7.32 ( 1H, m), 7.35-7.44 (1H, m), 7.47-7.60 (2H, m), 7.61-7.71 (1H, m), 8.07-8, 15 (2H, m), 8.19 (IN, dd, U-81, 1.3 Gu).

Example 546

Preparation of M-(1-(hydroxyacetyl)piperidin-4-yl|methyl)-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H- pyrrolo|3,2-s|quinoline-2-carboxamide (6)

UA

M on

Me, N

X xx OMe

M (in) x

By a procedure similar to that of Example 511, the title compound (77 mg, 41 95) was obtained as a white solid from the compound of Example 544 (200 mg, 0.34 mmol), 8M aqueous sodium hydroxide solution (1 .8 ml), THF (3.6 ml) and ethanol (13 ml). "H-NMR (300 MHz, DMSO-α) 6: 0.99-1.26 (2H, m), 1.65-1.93 (ZH, m), 2.57-2.71 (1H, m), 2.87-3.01 (1Н, m), 3.18-3.27 (2Н, m), 3.65-3.75 (1Н, m), 3.98 (ЗН, с) , 4.07 (2H, t, 9-54 Gu), 4.27-4.40 (4H, m), 4.41-4.50 (IN, m), 5.97 (2H, s), 7.25-7.42 (2H, m), 7.44-7.53 (1H, m), 7.59-7.68 (2H, m), 7.71-7.81 (1H, m ), 8.07 (1H, t, 3-6.0 Hz), 8.13-8.21 (2H, m), 8.37 (1H, dd, 9U-8.3, 1.1 Hz) .

Example 547

Preparation of M-(1-(hydroxyacetyl)piperidin-4-yl|-3-methoxy-M, 1-dimethyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H- pyrrolo|3,2-c|quinoline-2-carboxamide

(0) on

M

Me, yo

M. e

X xx OMe mo x

By a procedure similar to that of Example 511, the title compound (117 mg, 62 95) was obtained as a white solid from the compound of Example 545 (205 mg, 0.35 mmol), 8M aqueous sodium hydroxide solution (1 .8 ml), THF (3.6 ml) and ethanol (13 ml). "H-NMR (300 MHz, SOSIz) 5: 1.65-2.01 (4H, m), 2.78-2.92 (1H, m), 2.99-3.09 (ZH, m) , 3.12-3.27 (1Н, m), 3.48-3.69 (2Н, m), 3.99-4.04 (ЗН, m), 4.04-4.11 (ЗН, m), 4.14-4.30 (2H, m), 4.61-4.88 (2H, m), 5.89 (2H, s), 7.06 (1H, d, U9-8, 7 Hz), 7.22-7.32 (1H, m), 7.35-7.44 (1H, m), 7.54 (2H, t, 9U-7.6 Hz), 7.62- 7.72 (1H, m), 8.11 (2H, d, 9-7.6 Hz), 8.19 (1H, dd, U-8.3, 1.3 Hz).

Example 548

Preparation of M-(trans-2-Khydroxyacetyl)amino|cyclohexyl)-3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno|3,2-s|quinoline-2 -carboxamide o; (/ o) ik 5- NN he same tOME mori

By a procedure similar to that of Example 508, the title compound (88 mg, 58 95) was obtained as white crystals from the compound of Example 530 (150 mg, 0.26 mmol). "H-NMR (300 MHz, DMSO-dv) 6: 1.20-1.50 (6H, m), 1.70 (2H, w s), 1.87 (1H, d, 9U-11.1 Gu), 2.05 (IN, d, 3-9.6 Gu), 3.72-3.94 (7Н, m), 4.31 (ЗН, с), 5.48 (1Н, т, 9У -5.7 Hz), 5.97 (2H, s), 7.28-7.39 (2H, m), 7.47 (1H, t, 9U-7.8 Hz), 7.61-7 ... m), 8.137 (1H, d,

U-7.2 Hz).

Example 549

Preparation of /- M-(2-(1-(hydroxyacetyl)pyrrolidin-2-yl|ethyl)-3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno|3 ,2-quinoline-2-carboxamide

M o i Y Ton

M (c)

N

R z tOME

Mo r

By a procedure similar to that of Example 508, the title compound (70 mg, 51 95) was obtained as white crystals from the compound of Example 528 (150 mg, 0.25 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.50-2.00 (7Н, m), 3.00-3.15 (1Н, m), 3.30-3.45 (1Н, m), 3.55-3.70 (1N, m), 4.02-4.25 (7N, m), 4.52 (1N, t, U-5.3 Hz), 6.00 (2N , c), 7.35 (1H, t, 9U-7.5 Hz), 7.49 (1H, d, 9U-8.4 Gu), 7.56-7.67 (2H, m), 7 .77 (1H, t, U9-7.2 Hz), 8.05 (1H, d, U-7.8 Hz), 8.18 (2H, d, 9U-7.8 Gu), 8.46 (1H, t, 9U-5,3

Gu).

Example 550

Preparation of /-M-/1-(hydroxyacetyl)pyrrolidin-3-yl|Imethyl)-3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno|3,2- Cyquinoline-2-carboxamide (c)

The United Nations

M

(c) K-

M

5-4 хи тОМе

Mm'o ri

By a procedure similar to that of Example 508, the title compound (31 mg, 29 95) was obtained as white crystals from the compound of Example 529 (120 mg, 0.20 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.58-1.76 (1H, m), 1.90-2.10 (1H, m), 2.50-2.65 (1H, m), 3.11-3.17 (1Н, m), 3.30-3.65 (5Н, m), 3.99 (2Н, d, 9-42 Gu), 4.03 (ЗН, d , U-0.9 Gu), 4.46 (1H, t, U-4.8 Hz), 6.00 (2H, s), 7.35 (IN, t, U-7.5 Hu), 7.49 (1H, d, U-8.4 Hu), 7.56-7.67 (ZH, m), 7.77 (1H, t, U-7.5 Hu), 8.05 (1H , d, 9U-7.5

Hz), 8.18 (ZN, d, 9U-7.5 Hz).

Example 551

Preparation of M-(1-(hydroxyacetyl)azetidin-3-yl|-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo| 3,2-s|quinoline-2-carboxamide

With x

M on

Me. M -N same tOME mo ri

By a procedure similar to that of Example 508, the title compound (58 mg, 64 95) was obtained as white crystals from the compound of Example 531 (100 mg, 0.18 mmol). "H-NMR (300 MHz, DMSO-α) 6: 3.28-3.44 (2H, m), 3.84-3.86 (5H, m), 4.22 (1H, t, U- 6.3 Hz), 4.36 (ZH, s), 4.39-4.43 (2H, m), 5.55 (1H, t, U-5.7 Gu), 5.96 (2H, s), 7.30-7.40 (2H, m), 7.48 (1H, t, 9U-7.5 Hz), 7.63 (2H, t, 7.5 Hz), 7.76 ( 1H, t, 9U-7.5 Hz), 7.90 (1H, t, 9U-6.2 Hz), 8.16-8.19 (2H, m), 8.40 (1H, dd, U -8,1,0,9 Gu).

Example 552

Preparation of 2-(1,4-dioxa-8-azaspiro(4,5|)dec-8-ylcarbonyl)-3-methoxy-1-methyl-5-(2-oxo-2-phenylethyl)-1,5- dihydro-4H-pyrrolo|3,2-s|quinolin-4-one 6; oh

M x (8;

In OMe

M (in) x

By a procedure similar to that of Example 25, the title compound (279 mg, 60 95) was obtained as a white solid from the compound of Auxiliary Example 28 (350 mg, 0.90 mmol), 1,4-dioxa-8 -azaspiro|4,5|decane (154 mg, 1.1 mmol), NOVI (146 mg, 1.1 mmol), MUZSO (206 mg, 1.1 mmol), and DMF (10 mL). "H-NMR (300 MHz, SOS") 6: 1.72-1.88 (AN, m), 3.64-3.77 (2H, m), 3.82-3.96 (2H, m ), 3.98-4.02 (AN, m), 4.03 (ZN, s), 4.09 (ZN, s), 5.89 (2H, w s), 7.01-7.10 (1H, m), 7.19-7.30 (1H, m), 7.34-7.42 (1H, m), 7.49-7.58 (2H, m), 7.61-7 .69 (1H, m), 8.06-8.14 (2H, m), 8.19 (1H, dd, U-8.3, 1.3 Hz).

Example 553

Preparation of /3-methoxy-1-methyl-5-(2-oxo-2-phenylethyl)-2-(piperazin-1-ylcarbonyl)-1,5-dihydro-4H-pyrrolo|3,2-c|quinoline- 4-one hydrochloride o / x

Me. MO Mn Her m-th M / xx OMe

Mo and

By a procedure similar to that of Example 542, the title compound (478 mg, 95 95) was prepared as a pale yellow solid from the compound of Example 680 (571 mg, 1.0 mmol), a 4M solution of hydrochloric acid in ethyl acetate (11 mL), ethyl acetate (8.0 mL), and methanol (8.0 mL). "H-NMR (300 MHz, DMSO-dv) 6: 3.07-3.27 (4Н, m), 3.65-3.78 (2Н, m), 3.81-3.96 (5Н, m), 4.05 (ZH, s), 5.98 (2H, s), 7.24-7.52 (ZH, m), 7.57-7.68 (2H, m), 7.71 -7.81 (1H, m), 8.08-8.24 (2H, m), 8.35 (1H, dd, U-8.2, 1.0 Hu), 9.20 (2H, w with).

Example 554

Preparation of 2-(4-13-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrole|3,2- sequinoline-2-ylcarbonyl )piperazin-1-yl)-2-oxoethyl acetate (F) and (c)

Me, M o

M KhM / o

IH ze xx OMe (in,

Mo x

By a procedure similar to that of Example 544, the title compound (34 mg, 10 95) was obtained as a white solid from the compound of Example 553 (300 mg, 0.61 mmol), acetoxyacetyl chloride (0.081 mL, 0. 76 mmol), triethylamine (0.23 ml, 1.7 mmol) and THF (13

ML). "H-NMR (300 MHz, DMSO-α) 6: 2.09 (ZH, s), 3.43-3.79 (8H, m), 3.91 (ZH, s), 4.03 (ZH , s), 4.76-4.88 (2H, m), 5.98 (2H, s), 7.25-7.51 (ZH, m), 7.59-7.68 (2H, m ), 7.71-7.80 (1H, m), 8.13-8.22 (2H, m), 8.30-8.38 (IN, m).

Example 555

Preparation of 8-fluoro-3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-M-piperidin-4-yl-4,5-dihydrothieno|3,2- sequinoline-2-carboxamide hydrochloride

N Her

My

R

Ehhh OMe

M (in) x

By a procedure similar to that of Example 542, the title compound (335 mg, 83 95) was obtained as a white solid from the compound of Example 673 (452 mg, 0.76 mmol), a 4 M solution of hydrochloride in ethyl acetate (6 .0 ml), THF (4.0 ml) and methanol (4.0 ml). "H-NMR (300 MHz, DMSO- av) 6: 1.70-1.91 (2H, m), 1.95-2.12 (2H, m), 2.93-3.13 (2H, m), 3.19-3.52 (2H, m), 3.95-4.22 (AN, m), 6.00 (2H, s), 7.41-7.52 (1H, m) , 7.53-7.71 (ЗН, m), 7.72-7.84 (1Н, m), 7.86-8.03 (2Н, m), 8.11-8.25 (2Н, m), 8.63 (2H, w s).

Example 556

Preparation of 2-I4-((8-fluoro-33-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno|3,2-c)quinolin-2-yl|carbonyl )amino)piperidin-1-yl|-2-oxoethyl acetate (c) about 0-4

In / Me

My

With x

Ehhh OMe

M (in) x

By a procedure similar to that of Example 544, the title compound (161 mg, 80 95) was obtained as a white solid from the compound of Example 555 (180 mg, 0.34 mmol), acetoxyacetyl chloride (0.046 mL, 0, 42 mmol), triethylamine (0.13 ml, 0.93 mmol) and THF (7.5

ML). "H-NMR (300 MHz, SOS") 6: 1.45-1.64 (2Н, m), 2.01-2.26 (5Н, m), 2.89-3.05 (1Н, m ), 3.15-3.34 (1Н, m),

C3.60-3.77 (1H, m), 4.15 (ZH, s), 4.20-4.34 (1H, m), 4.41-4.54 (1H, m), 4, 67-4.84 (2H, m), 5.85 (2H, s), 6.95-7.04 (1H, m), 7.16-7.24 (1H, m), 7.51- 7.62 (4H, m), 7.64-7.74 (1H, m), 8.06-8.14 (2H, m).

Example 557

Preparation of 2-I14-(C15-(cyclohexylmethyl)-3-methoxy-1-methyl-4-oxo-4,5-dihydro-1H-pyrrolo|3,2- sequinoline-2-ylcarbonyl)amino)piperidine-1 -yl|-2-oxoethyl acetate

With others

MO /o-

Me o)

Me. h

M j tOME su

A mixture of the compound of Example 672 (110 mg, 0.24 mmol), bromomethylcyclohexane (108 mg, 0.60 mmol), potassium carbonate (72 mg, 0.60 mmol), and DMF (3 mL) was stirred at 80 °C for 24 hours. . After cooling to room temperature, the reaction mixture was diluted with saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluate: ethyl acetate) to give the indicated in the title compound (34 mg, 16 95) as a colorless oil. "H-NMR (300 MHz, DMSO-α) 6: 1.05-1.20 (5H, m), 1.35-2.00 ( 9H, m), 2.09 (ZH, s), 2.90 (1H, t, 9U-11.4

Hz), 3.19 (TN, t, U-12.2 Hz), 3.70 (1Н, d, U-13.5 Hz), 3.97 (ЗН, с), 4.10-4, 40 (8H, m), 4.80 (2H, d, 9-21 Gu), 7.30 (IN, t, 9-7.5 Hz), 7.54-7.62 (2H, m), 7.96 (1H, d, U-7.8 Hu), 8.32 (1H, d, 9-7.8 Hu).

Example 558

Preparation of tert-butyl 4-(C3-methoxy-5-(4-methoxybenzyl)-1-methyl-4-oxo-4,5-dihydro-1H-pyrrolo|3,2-c)quinoline-2-ylcarbonyl) amino)piperidine-1-carboxylate o) -o

MO x-Me

Me Me o)

Me. h

M same tOME

Mmm

Meow.

By a method similar to that given in Example 25, the title compound (6.09 g, 74 95) as white crystals from the compound of Auxiliary Example 107 (5.65 g, 14.4 mmol) and 1-Boc-4 - aminopiperidine (5.77 g, 28.80 mmol). "H-NMR (300 MHz, DMSO-adv) 5: 1.32-1.53 (11H, m), 1.85 (2H, d, 9U-10.2 Hz), 2.85-3.10 (2H, m), 3.69 (ZN, s), 3.88 (2H, d, 9U-13.2 Hz), 3.95-4.05 (AN, m), 4.27 (ZN, s), 5.52 (2H, w s), 6.85 (2H, d, 9U-8.7 Hz), 7.14 (2H, d, 9-8.7 Gu), 7.27 (1H , t, 9U-7.1 Gu), 7.41-7.48 (2H, m), 7.96 (1H, d, 9-7.8 Hz), 8.32 (1H, d, 9U- 8.1 Hz).

Example 559

Preparation of 2-I4-(3-methoxy-5-(4-methoxybenzyl)-1-methyl-4-oxo-4,5-dihydro-1H-pyrrolo|3,2-syquinoline-2-ylcarbonyl)amino)piperidine - 1-yl|-2-oxoethyl acetate

Me at 0-mo

M sh,

Me. their m-. And that's it)

meo -

By a procedure similar to that of Example 123, the title compound (360 mg, 73 95) was obtained as a white solid from the compound of Example 681 (440 mg, 0.87 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.35-1.65 (2H, m), 1.72-1.95 (2H, m), 2.09 (ZH, s), 2 .91 (1H, t, 9-11.7

Hz), 3.20 (1N, t, 9U-12.0 Hz), 3.58-3.75 (AN, m), 4.00-4.20 (5N, m), 4.27 (ZN , c), 4.80 (2H, d, 9-24 Hz), 5.40- 5.60 (2H, w), 6.86 (2H, d, 9U-8.7 Hz), 7.14 (2H, d, U9-8.7 Hz), 7.27 (1H, td, 9-71, 2.1 Gu), 7.41-7.49 (2H, m), 8.00 (1H, d, 9U-8.1 Hz), 8.33 (1H, d, 9U-8.1 Gu).

Example 560

Preparation of M-(1-(3-hydroxy-3-methylbutanoyl)piperidin-4-yl|-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5- dihydro-1H-pyrrolo|3,2-s|quinoline-2-carboxamide

Me Me oh, he

WITH

In M

Me, m-n zt OMe

More

By a procedure similar to that of Example 518, the title compound (109 mg, 60 95) was obtained as a white powder from the compound of Example 77 (150 mg, 0.317 mmol) and 3-hydroxy-3-methylbutanoic acid (45, 0 mg, 0.381 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.18 (6Н, s), 1.33-1.63 (2Н, m), 1.79-1.97 (2Н, m), 2 .43-2.52 (2H, m), 2.81-2.96 (1H, m), 3.14-3.29 (1H, m), 3.90-4.00 (4H, m) , 4.02-4.16 (1H, m), 4.22-4.36 (4H, m), 4.89 (1H, s), 5.97 (2H, s), 7.26-7 .41 (2H, m), 7.48 (1H, t, 9U-7.6 Hz), 7.63 (2H, t, 9U-7.5 Hz), 7.72-7.81 (1H, m), 7.95 (1H, d, 9U-7.9 Hz), 8.17 (2H, d, 9-7.7 Hz), 8.37 (1H, d, 9U-8.3 Hz) .

Example 561

Preparation of 3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-M-(1-propanoylpiperidin-4-yl)-4,5-dihydro-1H-pyrrolyl3,2-s |quinoline-2-carboxamide

(in;

U-E

M

Me, M - the same thing

M'o ri

By a procedure similar to that of Example 123, the title compound (90.2, 81 95) was obtained as a white powder from the compound of Example 77 (100 mg, 0.212 mmol) and propionyl chloride (20.2 μl, 0.233 mmol) . "H-NMR (300 MHz, DMSO-av) 6: 1.00 (ZH, t, 9U-7.5 Hu), 1.31-1.61 (2H, m), 1.77-1.96 (2H, m), 2.34 (2H, k, 97.4 Hz), 2.77-2.92 (1H, m), 3.10-3.25 (1H, m), 3.76- 3.88 (1H, m), 3.97 (ZH, s), 4.01-4.14 (1H, m), 4.19-4.29 (IN, m), 4.31 (ZH, s), 5.97 (2H, s), 7.26-7.41 (2H, m), 7.43-7.52 (1H, m), 7.63 (2H, t, U-7, 6 Hz), 7.71-7.81 (IN, m), 7.94 (1H, d, 9U-7.7 Gu), 8.12-8.22 (2H, m), 8.37 ( 1Н, дд, уУ-8,3,1,1 Hz).

Example 562

Preparation of 8-fluoro-M-(1-(hydroxyacetyl)piperidin-4-yl|-3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno|3,2- syquinoline-2-carboxamide with OH

M

55

M

WITH

H

E U OMe

I. M is) x

By a procedure similar to that of Example 511, the title compound (59 mg, 39 95) was obtained as a pale yellow solid from the compound of Example 556 (164 mg, 0.28 mmol). "H-NMR (300 MHz, SOS") 6: 1.42-1.63 (2H, m), 2.08-2.25 (2H, m), 2.97-3.26 (2H, m ), 3.47-3.59 (1H, m), 3.62 (IN, t, 9U-4.2 Gu), 4.14 (ЗН, s), 4.20 (2H, d, 9U- 4.0 Hu), 4.23-4.34 (1H, m), 4.45-4.58 (1H, m), 5.85 (2H, s), 6.94-7.04 (1H , m), 7.15-7.25 (1Н, m), 7.50-7.63 (4Н, m), 7.64-7.77 (1Н, m), 8.04-8.15 (2H, m).

Example 563

Preparation of 3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-N-(1-pyridin-4-ylpiperidin-4-yl)-4,5-dihydro-1H-pyrrolyl3 ,2-c|quinoline-2-carboxamide

M

; IN

M

M

I ate

X with OMe

M (in) x

To a solution of the compound of Auxiliary Example 28 (200 mg, 0.51 mmol), 1-pyridin-4-ylpiperidin-4-amine hydrochloride (128 mg, 0.51 mmol) and NOVI (83 mg, 0.61 mmol) in DMF (5.0 mL) was added M/U5CO (118 mg, 0.61 mmol) and triethylamine (0.23 mL, 16 mmol) while cooling on ice, and the mixture was stirred at room temperature for 67 hours. The reaction mixture was diluted with saturated saline and extracted 4 times with ethyl acetate. The extracts were combined and concentrated under reduced pressure. The residue was purified by chromatography on amino silica gel (eluate; ethyl acetate/hexane-40/60-00/0) and recrystallized from THF to give the title compound (121 mg, 43 95) as a pale purple solid. "H-NMR (300 MHz, DMSO-α) 6: 1.52-1.68 (2H, m), 1.87-1.98 (2H, m), 3.08 (2H, m), 3 .89 (2Н, m), 3.95 (ЗН, с), 4.04-4.17 (1Н, m), 4.31 (ЗН, с), 5.97 (2Н, с), 6, 85 (2H, d, 9U-6.4 Gu), 7.26-7.41 (2H, m), 7.43-7.53 (IN, m), 7.63 (2H, m), 7 .71-7.80 (1H, m), 7.98 (IN, d, 9U-7.7 Hz), 8.10-8.21 (4H, m), 8.37 (1H, d, 9 -74 Gu).

Example 564

Preparation of M-P-"hydroxyacetyl)piperidin-4-yl|-3-methoxy-5-(33-methoxybenzyl)-1-methyl-4-oxo-4,5-dihydro-1H-pyrrolo|3,2-s of quinoline-2-carboxamide

M sh,

Me, y

M

And with OMe

M (in) pu"

A mixture of the compound of Example 672 (110 mg, 0.24 mmol), 3-methoxybenzyl chloride (150 mg, 0.96 mmol), potassium carbonate (55 mg, 0.40 mmol) and DMF (5 mL) was stirred at 80 °C for 5 hours. After cooling to room temperature, 2M aqueous sodium hydroxide solution (1 mL) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over sulfate magnesium and concentrated under reduced pressure. white powder. "H-NMR (300 MHz, DMSO-α) 6: 1.40-1.65 (2H, m), 1.90 (2H, d, 9U-10.2 Hz), 2.93 ( 1H, t, U-10.2 Hz), 3.19 (IN, t, U-14.3 Hz), 3.60-3.70 (4H, m), 4.00-4.04 (AN , m), 4.04-4.10 (2Н, m), 4.30-4.36 (4Н, m), 4.52 (1Н, t, y -5.4 Gu), 5.58 (2H, w s), 6.69 (1H, d, U-8.4 Hz), 6.79 (2H, d, U-6.3 Hz), 7.20 (1H, t, U-8.4 Gu), 7.28 (1H, t, 3-6.3 Hz), 7.34-7.48 (2H, m), 7.89 (1H , d, U-8.1 Gu), 8. 34 (1H, d, U-8.4 Hz).

Example 565

Preparation of 3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-M-(2,2,6,6-tetramethylpiperidin-4-yl)-4,5-dihydro-1H -pyrrolo|3,2-c|quinoline-2-carboxamide

Me N

Me M

Me oh Me

Me. h

M hi tOME

M' r

By a procedure similar to that of Example 25, the title compound (410 mg, 76 95) was obtained as a white solid from the compound of Sub-Example 28 (400 mg, 1.02 mmol) and 4-amino-2, 2,6,6-tetramethylpiperidine (320 mg, 2.04 mmol). "H-NMR (300 MHz, DMSO-α) is: 0.86-1.24 (14Н, m), 1.78 (2Н, dd, 9У-12.6, 2.4 Hu), 3.96 (ZH, s), 4.28-4.31 (AN, m), 5.97 (2H, s), 7.29-7.47 (ZH, m), 7.63 (2H, t, 9U -7.5 Hz), 7.76 (2H, t, U-6.9 Gu), 8.17 (2H, d, 9U-7.5 Hz), 8.37 (1H, d, U-8 .4 Hz).

Example 566

Preparation of 3-methoxy-1-methyl-5-(2-oxo-2-phenylethyl)-2-((4-oxopiperidin-1-yl)ucarbonyl|-1,5-dihydro-4H-pyrrole|3,2- c|quinolin-4-one o) 00

MORE Щх ОМе ММ и

A solution of the compound of Example 552 (285 mg, 0.55 mmol) and 5M hydrochloric acid (3.0 mL) in THF (6.0 mL) was stirred at room temperature for 2 hours. 5M hydrochloric acid (1.5 ml) was added and the mixture was stirred at room temperature for 2 hours. 5M hydrochloric acid (1.5 ml) was added and the mixture was stirred at room temperature for 3.5 hours and concentrated under reduced pressure. The residue was basified with saturated sodium bicarbonate solution and extracted twice with ethyl acetate. The extracts were combined, washed with saturated saline and concentrated under reduced pressure. The residue was washed with water and recrystallized from methanol-diethyl ether to give the title compound (123 mg, 47 95) as a white solid.

"H-NMR (300 MHz, SOS") 6: 1.78-1.93 (3H, m), 1.95-1.99 (1H, m), 3.58-3.73 (2H, m ), 3.79-3.94 (2Н, m), 4.03 (ЗН, с), 4.07-4.11 (ЗН, m), 5.90 (2Н, с), 7.02- 7.11 (1H, m), 7.19-7.30 (1H, m), 7.34-7.43 (1H, m), 7.49-7.58 (2H, m), 7, 61-7.70 (1H, m), 8.07-8.14 (2H, m), 8.16-8.26 (1H, m).

Example 567

Preparation of M-P1-(M,M-dimethylglycyl)piperidin-4-yl|-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H -pyrrolo|3,2-c|quinoline-2-carboxamide

Me, x M-Me

M

Me, y

M

X xx OMe

M (in) x

By a procedure similar to that of Example 25, the title compound (125 mg, 57 95) was prepared as a pale purple solid from the compound of Example 77 (200 mg, 0.39 mmol) and M,M-dimethylglycine (49 mg, 0.47 mmol). "H-NMR (300 MHz, SOS") 6: 1.40-1.64 (2H, m), 1.99-2.17 (2H, m), 2.31 (6H, s), 2, 90-3.05 (1H, m), 3.08-3.21 (2H, m), 3.22-3.36 (1H, m), 3.99-4.11 (1H, m), 4.14 (ЗН, с), 4.18-4.29 (1Н, m), 4.36-4.45 (1Н, m), 4.47 (ЗН, с), 5.88 (2Н, d, 9U-4.2 Hz), 7.05 (1Н, d, 97.7 Hz), 7.20-7.32 (1Н, m), 7.37-7.46 (1Н, m), 7.50-7.59 (2H, m), 7.62-7.73 (2H, m), 8.06-8.16 (2H, m), 8.26 (1H, dd, 9U-8 ,3, 1.3 Hz).

Example 568

Preparation of M-(1-(3-ethoxypropanoyl)piperidin-4-yl|-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H- pyrrolo|3,2-s|quinoline-2-carboxamide fu

M shk,

Me, uh

MORE with OME mo h

By a procedure similar to that of Example 25, the title compound (159 mg, 70 95) was obtained as a pale purple solid from the compound of Example 77 (200 mg, 0.39 mmol) and 3-ethoxypropanoic acid ( 56 mg, 0.47 mmol). "H-NMR (300 MHz, DMSO-av) 6: 1.09 (ZH, t, 9U-7.0 Gu), 1.36-1.60 (2H, m), 1.80-1.96 (2H, m), 2.54-2.63 (2H, m), 2.78-2.92 (1H, m), 3.13-3.26 (1H, m), 3.42 (2H , k, 9U-6.9 Hu), 3.59 (2H, t, 9U-6.7 Hu), 3.81-3.91 (1H, m), 3.96 (ZH, s), 4 ,02-4.14 (1Н, m), 4.18-4.27 (1Н, m), 4.31 (ЗН, с), 5.97 (2Н, с), 7.26-7.41 (2H, m), 7.44-7.53 (IN, m), 7.58-7.68 (2H, m), 7.72-7.80 (1H, m), 7.94 (1H , d, 9U-7.9 Hu), 8.12-8.21 (2H, m), 8.37 (1H, dd, 9U-8.3, 1.3 Hu).

Example 569

Preparation of M-P-"hydroxyacetyl)piperidin-4-yl|-3-methoxy-5-(2-methoxybenzyl)-1-methyl-4-oxo-4,5-dihydro-1H-pyrrolo|3,2-s |quinoline-2-carboxamide

In H

M On shO,

Me. M m- same tOME

Mmm and Ome

To a solution of the compound of Example 570 (40 mg, 0.07 mmol) in THF (1 mL)-methanol (1 mL) was added 2M sodium hydroxide solution (1 mL) and the mixture was stirred at room temperature for 1 hour.

The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. By recrystallization from ethyl acetate-hexane, the title compound (30 mg, 80 95) was obtained as white crystals. "H-NMR (300 MHz, DMSO-α) 6: 1.50-1.60 (2H, m), 1.90 (2H, d, 9-10.2 Hz), 2.93 (1H, t , U-12.5 Hu), 3.15 (IN, t, 9U-12.5 Hz), 3.67 (1Н, d, 9U-13.2 Hu), 3.95 (ЗН, с), 4.00 (ZN, s), 4.05-4.20 (ZN, m), 4.20-4.30 (AN, m), 4.51 (1H, t, 9U-5.4 Gu) , 5.47 (2H, s), 6.50 (1H, d, 9U-7.5 Hz), 6.75 (1H, t, U-7.5 Gu), 7.09 (1H, d, U-84 Hz), 7.21-7.31 (ZH, m), 7.44 (1H, t, U-7.8 Gu), 7.97 (1H, d, U-7.8 Hz) , 8. 36 (1H, d, 9U-8.1 Hz).

Example 570

Preparation of 2-I4-(3-methoxy-5-(2-methoxybenzyl)-1-methyl-4-oxo-4,5-dihydro-1H-pyrrolo|3,2-si|quinoline-2-ylcarbonyl)amino )piperidin-1-yl|-2-oxoethyl acetate

AND

And (c) mo 0-4

Me (o)

M

M

X that OMe

Moto ai

By a procedure similar to that of Example 557, an amorphous solid (90 mg) was obtained from the compound of Example 672 (120 mg, 0.24 mmol), 2-methoxybenzyl chloride (50 95 solution in dichloromethane; 0.1 ml, 0, 79 mmol) and potassium carbonate (110 mg, 0.79 mmol). By recrystallization from ethyl acetate-diisopropyl ether, the title compound (44 mg, 29 95) was obtained as white crystals. "H-NMR (300 MHz, DMSO-α) 6: 1.50-1.70 (2H, m), 2.07-2.28 (5H, m), 3.04 (1H, t, 9U- 11.1 Gu), 3.29 (IN, t, 911.1 Gu), 3.70 (1H, d, 9U-14.4 Hz), 3.99 (ZN, s), 4.21-4 .28 (AN, m), 4.40-4.56 (4H, m), 4.78 (2H, s), 5.62

(2H, w s), 6.77 (2H, d, uU-4.2 Gu), 6.95 (1H, d, U-10.8 Hz), 7.19-7.42 (4H, m ), 7.77 (1TN, d, 9U-7.8 Hz), 8. 25 (IN, dd, U-8,4,1,2 Gu).

Example 571

Production // 3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-M-(tetrahydro-2H-thiopyran-4-yl)-4,5-dihydro-1H-pyrrolo |3,2-c) quinoline-2-carboxamide

M

Me " N hi tOME

Mm'o r

By a method similar to that given in Example 25, the title compound (2.51 g, 90 95) was obtained as a white solid from the compound of Auxiliary Example 28 (2.22 g, 5.69 mmol) and tetrahydrothiopyran- 4-ylamine (1.0 g, 8.53 mmol). "H-NMR (300 MHz, DMSO-av) 6: 1.63-1.77 (2H, m), 1.99-2.17 (2H, m), 2.66-2.78 (AN, m), 3.87-3.97 (4Н, m), 4.30 (ЗН, с), 5.97 (2Н, с), 7.28-7.39 (2Н, m), 7.47 (1H, td, U-7.8, 1.2 Hz), 7.63 (2H, t, 9U-7.5 Gu), 7.76 (IN, t, U-8.1 Hz), 7 .97 (1H, d, 9U-8.1 Hz), 8.16-8.18 (2H, m), 8.36 (1H, dd, U-8.4, 1.2 Hz).

Example 572

Preparation of 3-methoxy-1-methyl-N-(1-oxidotetrahydro-2H-thiopyran-4-yl)-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo |3,2-s|quinoline-2-carboxamide o

with what

Me. M

M same tOME

Mo r

A solution of the compound of Example 571 (200 mg, 0.41 mmol) and tSRPA (containing 70 95 water; 106 mg, 0.43 mmol) in ethyl acetate (25 mL) was stirred at 0 °C for 1 hour. The reaction mixture was diluted with saturated aq. sodium bicarbonate solution and extracted with ethyl acetate.The extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure.

By recrystallization of the residue from ethyl acetate-hexane, the title compound (54 mg, 26 g) was obtained as white crystals. "H-NMR (300 MHz, DMSO-α) 6: 1.88 (2H, d, 9-12.9 Hz), 2.20 (2H, k, 9-12.7 Hz), 2.70- 3.00 (4H, m), 3.97-4.06 (4H, m), 4.29 (ZH, s), 5.97 (2H, s), 7.29-7.40 (2H, m), 7.48 (1H, t, U-7.5 Hz), 7.63 (2H, t, U9-7.5 Gu), 7.76 (IN, t, 9-7.5 Hz) , 8.05 (1H, d, 9U-8.1 Hz), 8.16-8.19 (2H, m), 8.37 (1H, d, 9U-7.5 Gu).

Example 573

Preparation of /- M-P1-(ethoxyacetyl)piperidin-4-yl|-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo |3,2-s|quinoline-2-carboxamide x OEI

M

Me, M

M

And xx OMe

M (6) x

By a procedure similar to that of Example 25, the title compound (134 mg, 61 95) was obtained as a white solid from the compound of Example 77 (200 mg, 0.39 mmol) and ethoxyacetic acid (0.045 mL, 0 .47 mmol). "H-NMR (300 MHz, DMSO-av) 6: 1.14 (ZH, t, 9U-7.0 Gu), 1.35-1.64 (2H, m), 1.81-1.97 (2H, m), 2.81-2.95 (IN, m), 3.09-3.24 (1H, m), 3.42-3.55 (2H, m), 3.73-3 .85 (1Н, m), 3.96 (ЗН, с), 4.02-4.25 (4Н, m), 4.31 (ЗН, с), 5.97 (2Н, с), 7, 26-7.41 (2H, m), 7.43-7.53 (1H, m), 7.58-7.68 (2H, m), 7.71-7.81 (1H, m), 7.95 (1H, d, 9-7.7

Hu), 8.12-8.22 (2H, m), 8.37 (1H, dd, U-8.2, 1.2 Hz).

Example 574

Preparation of 3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-M-(1-pyridin-4-ylpiperidin-4-yl)-4,5-dihydro-1H-pyrrolo |3,2-c) quinoline-2-carboxamide hydrochloride

Mo Ne; IN

M sh,

Mke Y

X hu OMe

I, Me) x

A solution of the compound of Example 563 (250 mg, 0.46 mmol) and a 4M solution of the hydrochloride in ethyl acetate (0.114 mL, 0.46 mmol) in methanol (3.0 mL)-ethyl acetate (3.0 mL) was stirred at room temperature for 10 minutes The reaction mixture was concentrated under reduced pressure and the residue was recrystallized from methanol-diethyl ether to give the title compound (45 mg, 17 95) as a white solid. "H-NMR (300 MHz, DMSO-dv) 6: 1.54-1.74 (2H, m), 1.95-2.10 (2H, m), 3.36-3.48 (2H, m), 3.96 (ZH, s), 4.11-4.36 (6Н, m), 5.97 (2Н, s), 7.17-7.27 (2Н, m), 7.28 -7.42 (2H, m), 7.43-7.53 (1H, m), 7.58-7.69 (2H, m), 7.71-7.82 (IN, m), 8 .00 (1H, d, 9U-7.7 Gu), 8.12-8.19 (2H, m), 8.21-8.28 (2H, m), 8.38 (1H, dd, U -8,3,1,1 Gu), 13,40 (IN, w s).

Example 575

Preparation of 3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-N-(1-phenylpiperidin-4-yl)-4,5-dihydro-1H-pyrrolyl3,2-s |quinoline-2-carboxamide

M

M

Me and

X xx OMe

ICF) x

A solution of the compound of Example 77 (200 mg, 0.42 mmol), iodobenzene (0.50 ml), tricydibenzylideneacetone)dipalladium (0) (38 mg, 0.042 mmol), x-rpo5 (40 mg, 0.085 mmol) and tert-butoxide sodium (102 mg, 1.1 mmol) in tert-butanol (4.0 ml) was stirred under microwave radiation at 130 "C for 35 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate. The extracts were combined, dried over magnesium sulfate and concentrated under reduced pressure.The residue was purified by chromatography on amino silica gel (eluate; ethyl acetate/hexane-30/70-100/0) and recrystallized from ethyl acetate to give the title compound (70 mg, 30 95) as a white solid . "H-NMR (300 MHz, SOCI3) 5: 1.67-1.85 (2H, m), 2.09-2.25 (2H, m), 2.92-3.08 (2H, m ), 3.53-3.69 (2Н, m), 4.06-4.25 (4Н, m), 4.48 (ЗН, с), 5.88 (2Н, с), 6.82- 6.92 (1Н, m), 6.94-7.09 (ЗН, m), 7.20-7.32 (ЗН, m), 7.35-7.46 (1Н, m), 7, 49-7.59 (2H, m), 7.61-7.81 (2H, m), 8.03-8.16 (2H, m), 8.26 (1H, dd, 9U-8.3 , 1.3 Hz).

Example 576

Preparation of 3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-N-(1-prolylpiperidin-4-yl)-4,5-dihydro-1H-pyrrolyl3,2-s |quinoline-2-carboxamide hydrochloride

N

-and

M

NOI sh,

Mke N

X xx OMe

I. She; h

To a solution of the compound of Example 77 (300 mg, 0.59 mmol), 1-(tert-butoxycarbonyl)proline (152 mg, 0.71 mmol) and NOVI (96 mg, 0.71 mmol) in DMF (7.5 mL ) were added MUZSO (136 mg, 0.71 mmol) and triethylamine (0.18 mL, 1.3 mmol) while cooling on ice, and the mixture was stirred at room temperature for 17 h. The reaction mixture was diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate. The extracts were combined, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on amino silica gel (eluate; ethyl acetate/hexane-20/80-100/0). The obtained compound was dissolved in methanol (4.5 ml), a 4M solution of hydrochloride in ethyl acetate (4.5 ml) was added and the mixture was stirred at room temperature for 7 hours. The reaction mixture was concentrated under reduced pressure and recrystallized from methanol-diethyl ether to give the title compound (234 mg, 65 95) as a white solid. "H-NMR (300 MHz, DMSO-av) 6: 1.37-1.69 (2H, m), 1.69-1.84 (1H, m), 1.84-2.05 (AN, m), 2.29-2.46 (1Н, m), 2.91-3.27 (АН, m), 3.75-3.91 (1Н, m), 3.97 (ЗН, d, 9-1.5 Hz), 4.06-4.29 (2Н, m), 4.32 (ЗН, d, 9У-3.2 Hz), 4.48-4.67 (1Н, m), 5.97 (2H, s), 7.27-7.43 (2H, m), 7.44-7.54 (1H, m), 7.56-7.70 (2H, m), 7, 70-7.83 (1H, m), 7.97 (1H, dd, 9uU-11.8, 7.8 Gu), 8.08-8.26 (2H, m), 8.38 (1H, dd, 9U-8.3, 1.1 Hz), 8.93 (2H, w s).

Example 577

Preparation of 3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-N-(1-pyridin-4-ylpiperidin-4-yl)-4,5-dihydro-1H-pyrrolyl3 ,2-c|quinoline-2-carboxamide methanesulfonate

M

; IN

M

/ mon

M

Me, N

X xx OMe

I. M c) x

By a procedure similar to that of Example 574, the title compound (142 mg, 36 95) was obtained as a pale yellow solid from the compound of Example 563 (333 mg, 0.61 mmol), methanesulfonic acid (0.041 mL , 0.64 mmol). "H-NMR (300 MHz, DMSO-dv) 6: 1.55-1.73 (2H, m), 1.96-2.09 (2H, m), 2.30 (ZH, s), 3 .36-3.49 (2H, m), 3.96 (ZH, s), 4.14-4.37 (6H, m), 5.97 (2H, s), 7.17-7.27 (2H, m), 7.28-7.42 (2H, m), 7.43-7.52 (1H, m), 7.57-7.68 (2H, m), 7.71-7 .81 (1H, m), 8.00 (1H, d, 9-7.9 Gu), 8.11-8.19 (2H, m), 8.21-8.28 (2H, m), 8.38 (1H, dd, y-8.2, 1.2 Gu), 13.22 (IN, w s).

Example 578

Preparation of 3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-M-(1-(1,3-thiazol-2-yl)piperidin-4-yl|-4, 5-dihydro-1H-pyrrolo|3,2-s|quinoline-2-carboxamide 875)

M sh,

M

Me, N

X xx OMe

M (in) x

By a method similar to that given in Example 25, the title compound (152 mg, 53 95) was obtained as a white solid from the compound of Auxiliary Example 28

(200 mg, 0.51 mmol) and 1-(1,3-thiazol-2-yl)piperidin-4-amine hydrochloride (124 mg, 0.56 mmol). "H-NMR (300 MHz, DMSO- av) 6: 1.58-1.79 (2H, m), 1.90-2.04 (2H, m), 3.15-3.28 (2H, m), 3.81-3.92 (2Н, m), 3.96 (ЗН, с), 4.03-4.18 (1Н, m), 4.31 (ЗН, с), 5.97 (2H, s), 6.83 (1H, d, 9U-3.6 Hz), 7.16 (1TN, d, 9U-3.6 Hz), 7.21-1.A1 (2H, m) , 7.44-7.52 (1H, m), 7.58-7.68 (2H, m), 7.70-7.82 (1H, m), 8.00 (1H, d, U- 7.9 Hz), 8.10-8.23 (2H, m), 8.37 (1H, dd, U-8.3, 1.3 Hz).

Example 579

Preparation of 8-fluoro-M-(/1-(2-hydroxyethyl)piperidin-4-yl|-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5 -dihydro-1H-pyrrole|3,2-c)quinoline-2-carboxamide di

M

KO,

Me, M

M

Their

Well, Ome

MF) x

A solution of the compound of Example 675 (300 mg, 0.57 mmol), potassium carbonate (629 mg, 4.6 mmol) and triethylamine (0.11 mL, 0.76 mmol) in DMF (13 mL) was stirred at 100 °C for 5 minutes and 2-bromoethanol (0.16 mL, 2.3 mmol) was added. After stirring at 100 "C for 1.5 hours, the reaction mixture was concentrated under reduced pressure. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The extracts were combined, washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on amino silica gel (eluate; methanol/ethyl acetate-0/100-5/95) and recrystallized from THF-diethyl ether to give the title compound (205 mg, 51 90) as a white solid. "H-NMR (300 MHz, DMSO-dv) 6: 1.47-1.67 (2H, m), 1.75-1.89 (2H, m), 2.08-2.25 (2H, m), 2.40 (2H, t, 96.3 Gu), 2.70-2.86 (2H, m), 3.49 (2H, k, U-6.1 Hz), 3.74- 3.89 (1H, m), 3.97 (ZH, s), 4.31 (ZH, s), 4.38 (1H, t, y-5.4 Hz), 5.97 (2H, s ), 7.28-7.40 (1H, m), 7.40-7.49 (1H, m), 7.58-7.68 (2H, m), 7.71-7.82 (1H , m), 7.92 (1H, d, 9-7.7 Gu), 8.05-8.23 (ZH, m).

Example 580

Preparation of 3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-M-(1-(tetrahydrofuran-2-ylcarbonyl)piperidin-4-yl|-4, 5-dihydro- 1H-pyrrolo|3,2-c|quinoline-2-carboxamide o o de shkO,

M

Me, in N

X х ОМе

Mo x

By a procedure similar to that of Example 25, the title compound (41 mg, 17 U5) was obtained as a white solid from the compound of Auxiliary Example 77 (200 mg, 0.42 mmol) and tetrahydrofuran-2-carboxylic acid (0.049 mL, 0.51 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.34-1.63 (2H, m), 1.74-1.95 (4H, m), 1.96-2.12 (2H, m), 2.78-2.97 (1Н, m), 3.09-3.28 (1Н, m), 3.68-3.86 (2Н, m), 3.88-4.02 ( AN, m), 4.03-4.27 (2Н, m), 4.28-4.35 (ЗН, m), 4.68 (1Н, dd, U-7.4, 5.9 Gu) , 5.97 (2H, s), 7.26-7.41 (2H, m), 7.43-7.53 (1H, m), 7.58-7.68 (2H, m), 7 ,71-7.81 (1H, m), 7.89-8.03 (1H, m), 8.12-8.22 (2H, m), 8.37 (1H, dd, 9U-8, 3, 1.1 Hz).

Example 581

Preparation of 3-methoxy-1-methyl-M-11-(4-methylsulfonyl)phenyl|piperidin-4-yl)-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro- 1H-pyrrolo|3,2-s|quinoline-2-carboxamide o

Sho)

M what

M

Me and

Х ш ОМе ше)

H

By a procedure similar to that of Example 575, the title compound (28 mg, 8.0 95) was obtained as a white solid from the compound of Example 77 (260 mg, 0.55 mmol) and 1-bromo-4 -(methylsulfonyl)benzene (259 mg, 1.1 mmol). "H-NMR (300 MHz, DMSO- av) 6: 1.54-1.72 (2Н, m), 1.88-2.04 (2Н, m), 3.05-3.20 (5Н, m), 3.85-3.99 (BN, m), 4.04-4.22 (1Н, m), 4.31 (ЗН, с), 5.97 (2Н, с), 7.06 -7.17 (2H, m), 7.26-7.41 (2H, m), 7.43-7.52 (1H, m), 7.57-7.11 (AN, m), 7 .72-7.82 (1H, m), 7.99 (1H, d, 9U-7.9 Hz), 8.14-8.23 (2H, m), 8.37 (1H, dd, 981 ,11 Gu).

Example 582

Preparation of 3-methoxy-1-methyl-N-(1-(2-methylpyridin-4-yl)piperidin-4-yl|-4-oxo-5-(2-oxo-2-phenylethyl)-4,5- dihydro-1H-pyrrolo|3,2-s|quinoline-2-carboxamide

M

M sh,

Me, them

M

X xx OMe

And SHKF) d

By a procedure similar to that of Example 575, the title compound (51 mg, 14 95) was obtained as a white solid from the compound of Auxiliary Example 77 (300 mg, 0.64 mmol) and 4-bromo-2- of methylpyridine (0.15 ml, 1.3 mmol). "H-NMR (300 MHz, DMSO-dv) 6: 1.48-1.68 (2H, m), 1.84-1.98 (2H, m), 2.32 (ZH, s), 2 .95-3.14 (2Н, m), 3.80-3.91 (2Н, m), 3.95 (ЗН, с), 4.02-4.18 (1Н, m), 4.31 (ZH, s), 5.97 (2H, s), 6.62-6.70 (1H, m), 6.71-6.75 (IN, m), 7.24-7.41 (2H , m), 7.43-7.52 (1H, m), 7.58-7.67 (2H, m), 7.70-7.81 (1H, m), 7.92-8.06 (2H, m), 8.12-8.22 (2H, m), 8.37 (1H, dd, 9U-8.3, 1.1 Hz).

Example 583

Preparation of 3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-M-(1-pyrimidin-4-ylpiperidin-4-yl)-4,5-dihydro-1H-pyrrolo |3,2-s|quinoline-2-carboxamide

M v, -M

M chk,

M

Me, J

X xx OMe

I. MF) x

A solution of the compound of Example 77 (200 mg, 0.42 mmol), 4-chloropyrimidine (58 mg, 0.51 mmol) and triethylamine (0.12 mL, 0.85 mmol) in 2-propanol (4.0 mL) was heated under reflux for 23 hours. The reaction mixture was diluted with a saturated solution of sodium bicarbonate and extracted twice using a mixture of ethyl acetate-methanol solvents. The extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by amino silica gel chromatography (eluate; ethyl acetate/methanol--0/100-5/95) and recrystallized from THF to give the title compound (97 mg, 42 95) as a white solid. "H-NMR (300 MHz, DMSO-α) 6: 1.44-1.65 (2H, m), 1.88-2.02 (2H, m), 3.10-3.24 (2H, m), 3.95 (ZH, s), 4.08-4.23 (1H, m), 4.25-4.39 (5H, m), 5.97 (2H, s), 6.88 (1H, dd, 9U-6.4, 1.1 Hz), 7.26-7.41 (2H, m), 7.43-7.52 (IN, m), 7.58-7.68 (2H, m), 7.72-7.81 (1H, m), 7.97 (1H, d, 9U-7.9 Gu), 8.11-8.23 (ЗН, m), 8, 37 (1H, dd, 9U-8.3, 1.1 Gu), 8.49 (1H, s).

Example 584

Preparation of 8-fluoro-M-(1-(hydroxyacetyl)piperidin-4-yl|-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro- 1H-pyrrolo|3,2-s|quinoline-2-carboxamide dm

M sh,

M

Me, N

M

H

E HU OMe and ShKF) i

By a procedure similar to that of Example 511, the title compound (103 mg, 38 95) was obtained as a white solid from the compound of Example 676 (293 mg, 0.50 mmol). "H-NMR (300 MHz, DMSO-av) 6: 1.36-1.63 (2H, m), 1.81-1.96 (2H, m), 2.84-2.99 (1H, m), 3.06-3.20 (1Н, m), 3.61-3.74 (1Н, m), 3.95 (ЗН, с), 4.03-4.15 (ЗН, m) , 4.17-4.27 (1H, m), 4.30 (ZH, s), 4.52 (1H, t, 9U-5.5 Gu), 5.97 (2H, s), 7, 30-7.40 (1H, m), 7.41-7.49 (1H, m), 7.58-7.68 (2H, m), 7.71-7.80 (1H, m), 8.01 (1H, d, 9U-7.7

Hz), 8.07-8.21 (ZH, m).

Example 585

Preparation of /- M-/1-(hydroxyacetyl)piperidin-4-yl|-3-methoxy-1-methyl-4-oxo-5-(pyridin-2-ylmethyl)-4,5-dihydro-1H-pyrrolo| Z,2-c|quinoline-2-carboxamide

In him

M n,

Me, M

M s OMe

Mo

M

Go away

To a suspension of the compound of Example 672 (300 mg, 0.66 mmol) in DMF (5 mL) was added sodium hydride (60 90 in oil; 79 mg, 1.98 mmol) and the mixture was stirred at room temperature for 30 minutes.

2-Chloromethylpyridine hydrochloride (238 mg, 1.46 mmol) was added to the mixture and the mixture was stirred at 60 C for 16 hours. After cooling, the reaction mixture was diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate. The extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on amino silica gel (eluate; ethyl acetate), obtaining 2-14-(|3-methoxy-1-methyl-4-oxo-5-(pyridin-2-ylmethyl)-4,5-dihydro-1 H -pyrrolo|3,2-c|quinolin-2-ylcarbonyl)amino)piperidine-1-yl|-2-oxoethyl acetate (60 mg).

To a solution of 2-I4-(13-methoxy-1-methyl-4-oxo-5-(pyridin-2-ylmethyl)-4,5-dihydro-1H-pyrrole|3,2- sequinoline-2-ylcarbonylamino) of piperidin-1-yl|-2-oxoethyl acetate (60 mg) in THF (2 ml)-methanol (2 ml) was added 2M sodium hydroxide solution (2 ml) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate. The extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. By recrystallization from ethyl acetate-diisopropyl ether, the title compound (25 mg, 4595) was obtained as beige crystals.

"H-NMR (300 MHz, DMSO-α) 6: 1.40-1.60 (2H, m), 1.90 (2H, d, 9U-11.4 Hz), 2.93 (1H, t , 9U-11.2 Hz), 3.15 (IN, t, 9U-11.9 Gu), 3.67 (1H, d, U-13.8 Hz), 4.01-4.29 (TON , m), 4.52 (1H, t, U-5.4 Gu), 5.66 (2H, s), 7.11 (1H, d, U-7.8 Hz), 7.24-7 .31 (2H, m), 7.40-7 44 (2H, m), 7.71 (IN, td, 9U-7.5, 1.8 Hz), 7.97 (1H, d, U- 7.8 Gu), 8.34 (IN, d, U-8.1 Gu), 8.49-8.51 (1H, m).

Example 586

Preparation of /- M-/1-(hydroxyacetyl)piperidin-4-yl|-3-methoxy-1-methyl-4-oxo-5-(pyridin-4-ylmethyl)-4,5-dihydro-1H-pyrrolo| 3,2-s|quinoline-2-carboxamide about on

M what

M

Me, N

Their with OMe

I. MF) and

YAM

By a procedure similar to that of Example 585, the title compound (14 mg, 5 95) was obtained as beige crystals from the compound of Example 672 (300 mg, 0.66 mmol) and 4-chloromethylpyridine hydrochloride (130 mg, 0 .80 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.35-1.60 (2H, m), 1.90 (2H, d, 9U-11.4 Hz), 2.93 (1H, t , 9-12.4 Hz), 3.14 (IN, t, U-14.2 Hz), 3.60-3.75 (1H, m), 4.10-4.29 (TON, m) , 4.45-4.60 (1H, w), 5.63 (2H, s), 7.16 (2H, d, 9-51

Hz), 7.28-7.36 (2H, m), 7.46 (1H, t, U-8.1 Hz), 7.99 (1H, d, 9U-7.8 Hz), 8, 36 (1H, d, U-8.4 Gu), 8.48 (2H, d, 3-48 Hz).

Example 587

Preparation of 3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-M-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro-1H-pyrrolyl3,2 -c|quinoline-2-carboxamide (o) m,

Me. M

M- well tOME

Mo r

By a procedure similar to that of Example 25, the title compound (204 mg, 84 90) was obtained as white crystals from the compound of Auxiliary Example 28 (200 mg, 0.51 mmol) and 4-aminotetrahydropyran (62 mg, 0 .61 mmol). "H-NMR (300 MHz, DMSO-av) 6: 1.59 (2H, k, 9-10.0 Hu), 1.84 (2H, d, 9U-13.5 Hz), 3.44 ( 2H, t, 9U-11.0

Hz), 3.86 (2H, d, 9U-11.4 Hz), 3.97 (ЗН, s), 4.00-4.10 (1Н, m), 4.31 (ЗН, s), 5.97 (2H, s), 7.29-7.39 (2H, m), 7.48 (1H, t, 9-7.5 Gu), 7.63 (2H, t, 9U-7, 5 Hz), 7.76 (IN, t, 9U-7.1 Hz), 7.96 (1H, d, U-7.8 Gu), 8.17 (2H, d, 9U-7.5 Hz ), 8.37 (1H, d, 9-81 Gu).

Example 588

Preparation of tert-butyl 4-(3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo|3,2-c)quinoline- 2-ylcarbonyl)amino)-2-methylpiperidine-1-carboxylate

(F)

Me U-oh

MO x-Me

Me Me (F)

M

Me N

It's their toMe

I, She)ri

By a procedure similar to that of Example 25, the title compound (220 mg, 75 90) was obtained as white crystals from the compound of Auxiliary Example 28 (200 mg, 0.51 mmol) and 1-Boc-4-amino- 2-methylpiperidine (131 mg, 0.61 mmol). "H-NMR (300 MHz, DMSO-av) 6: 1.24 (ZH, d, U-6.9 Hz), 1.41 (9H, s), 1.65-1.95 (4H, m ), 3.13 (1H, t,

U-10.7 Hz), 3.73 (1H, d, U-13.2 Hz), 4.02 (ZH, s), 4.10-4.20 (2H, m), 4.35 ( ZN, s), 5.98 (2H, s), 7.30-7.41 (2H, m), 7.468 (IN, t, U9-7.2 Hz), 7.63 (2H, t, 9U -7.5 Gu), 7.76 (1TN, t, 9-7.5 Hz), 8.02 (1Н, d, U-6.6 Hz), 8.16-8.19 (2Н, m ), 8.38 (1H, d, 9U-7.2 Gu).

Example 589

Preparation of 3-methoxy-1-methyl-N-(2-methylpiperidin-4-yl)-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolyl3,2-s |quinoline-2-carboxamide hydrochloride

Me n

M

IF)

M

Me. s N NS hi tOME sho) ri

By a procedure similar to that of Example 61, the title compound (163 mg, 100 95) was obtained as white crystals from the compound of Example 588 (200 mg, 0.34 mmol). "H-NMR (300 MHz, DMSO-av) 5: 1.26 (ZH, d, 9U-6.3 Hz), 1.45-1.90 (ZH, m), 2.08 (2H, t , U-141 Hz), 3.04 (IN, t, 9U-11.9 Hz), 3.96 (ЗН, с), 4.04-4.14 (1Н, m), 4.28 (ЗН , c), 5.98 (2H, c), 7.29-7.40 (2H, m), 7.468 (IN, d, 9U-7.8 Gu), 7.64 (2H, t, 9U- 7.5 Hz), 7.76 (1H, t, U-7.5 Hz), 8.09 (1H, d, U-7.8 Hz), 8.16-8.19 (2H, m) , 8.37 (1H, d, U-8.4 Gu), 8.50-8.90 (2H, pc).

Example 590

Preparation of M-P1-(2-hydroxyethyl)-2-methylpiperidin-4-yl|-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro- 1H-pyrrolo|3,2-s|quinoline-2-carboxamide on

Me /Y- o, o

Me. M m-n same tOME

I Shk c) p

By a procedure similar to that of Example 79, the title compound (25 mg, 36 95) was obtained as white crystals from the compound of Example 589 (70 mg, 0.13 mmol). "H-NMR (300 MHz, DMSO-av) 6: 1.06 (ZH, d, 9U-6.3 Gu), 1.23 (1H, k, 9U-11.6 Hz), 1.40- 1.60 (1H, m), 1.85 (2H, d, 9U-10.8 Gu), 2.21-2.32 (ЗН, m), 2.74-2.83 (1H, m) , 2.96 (IN, t, 9U-12.3 Hz), 3.45-3.51 (2Н, m), 3.70- 3.90 (1Н, m), 3.98 (ЗН, s ), 4.30-4.38 (4H, m), 5.97 (2H, s), 7.29-7.45 (2H, m), 7.48 (IN, d, 9-7.5 Hu), 7.63 (2H, t, 9U9-7.5 Hz), 7.74-7.84 (2H, m), 8.17 (2H, d, 9-7.8 Hu), 8, 37 (1H, d, uU-8.4 Hz).

Example 591

Preparation of M-P1-"hydroxyacetyl)-2-methylpiperidin-4-yl|-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H- pyrrolo|3,2-s|quinoline-2-carboxamide o on

Me 3-7 o, o

Me. M m- with tOME

I. She)ri

By a procedure similar to that of Example 130, the title compound (35 mg, 40 95) was obtained as white crystals from the compound of Example 589 (80 mg, 0.15 mmol). "H-NMR (300 MHz, DMSO-av) 5: 1.28 (ZN, d, 9U-6.9 Hz), 1.70-1.95 (AN, m), 3.10-3.25 (1N, m), 4.03-4.15 (7N, m), 4.30-4.34 (4N, m), 4.50 (1TN, t, U-5.4 Hu), 5, 98 (2H, s), 7.30-7.41 (2H, m), 7.49 (1H, t, U-81 Gu), 7.63 (2H, t, 9U-7.5 Hz), 7.76 (1H, t, U-7.2 Gu), 8.07 (1H, d, U-6.6 Hz), 8.17 (2H, d, 9U-7.2 Hz), 8, 38 (1H, d, 9U-7.5 Hz).

Example 592

Preparation of /- M-(/1-(4-cyanophenyl)piperidin-4-yl|-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro -1H-pyrrolo|3,2-c|quinoline-2-carboxamide

SM

M shk,

M ko Ts

X xx OMe

And M is) I

A solution of the compound of Example 77 (300 mg, 0.64 mmol), 4-fluorobenzonitrile (115 mg, 0.95 mmol) and potassium carbonate (176 mg, 1.3 mmol) in M-methylpyrrolidone (3.0 mL) was stirred at 120 "C for 16.5 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure.

The residue was purified by chromatography on amino silica gel (eluate; ethyl acetate/hexane-30/70-100/0) and recrystallized from THF-diethyl ether to give the title compound (73 mg, 95) as a pale yellow solid. "H-NMR (300 MHz, DMSO- av) 6: 1.52-1.70 (2H, m), 1.87-2.03 (2H, m), 3.02-3.20 (2H, m), 3.81-4.00 (BN, m), 4.03-4.20 (1Н, m), 4.31 (ЗН, с), 5.97 (2Н, с), 6.98 -7.12 (2Н, m), 7.26-7.41 (2Н, m), 7.43-7.52 (1Н, m),

7.53-7.69 (4H, m), 7.71-7.82 (1H, m), 7.98 (1H, d, 9U-7.9 Gu), 8.12-8.22 ( 2H, m), 8.37 (1H, dd, U-8,4,1,2 Hz).

Example 593

Preparation of M-P1-«(hydroxyacetyl)piperidin-4-yl|-3-methoxy-1-methyl-4-oxo-5-|3- (trifluoromethoxy)benzyl|-4,5-dihydro-1H-pyrrolo|3 ,2-c|quinoline-2-carboxamide o

M on sh,

M

Me Ts

Their xx OMe

I, M are)

She

E E

According to a method similar to the method given in Example 570, 2-1A-(((3-methoxy-1-methyl-4-oxo-5-3-(trifluoromethoxy)benzyl|-4,5-dihydro-1H-pyrrolo |3,2-c)quinoline-2-ylcarbonyl)amino|piperidin-1-yl)-2-oxoethyl acetate (70 mg) was obtained as a colorless amorphous solid from the compound

Example 672 (500 mg, 1.10 mmol) and 3-trifluoromethoxybenzyl bromide (1.0 g, 3.92 mmol).

A solution of /2-(4-((3-methoxy-1-methyl-4-oxo-5-(3-«(trifluoromethoxy)benzyl-4,5-dihydro-1H-pyrrolo3,2- syquinoline-2-ylcarbonyl) )amino|piperidin-1-yl)y-2-oxoethyl acetate (70 mg) and potassium carbonate (77 mg, 0.55 mmol) in THF (2 mL)-methanol (1 mL)-water (1 mL) were stirred at at room temperature for 3 hours. The reaction mixture was diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (23 mg, 4 95) in the form of white crystals. "H-NMR (300 MHz, DMSO-α) 6: 1.35-1.65 (2Н, m), 1.85-1.95 (2Н, m), 2.93 (1H, t, 9U-11.7 Hz), 3.15 (IN, t, y-11.7 Gu), 3.68 (1H, d, 9U-12.3 Hz), 4.01-4 .29 (TON, m), 4.53 (1TN, t, 9U-5.4 Hz), 5.50-5.70 (2Н, w), 7.16- 7.33 (AN, m), 7.41-7.47 (ZH, m), 8.00 (1H, d, U-8.1 Hz), 8.36 (1H, d, 9U-8.1 Hz).

Example 594

Preparation of M-P1-(2-hydroxyethyl)piperidin-4-yl|-3-methoxy-4-oxo-5-(2-(1H-pyrrol-1-yl)ethyl|-4,5- dihydrothienoyl3,2- siIchinoline-2-carboxamide trifluoroacetate p

M what;

M

WITH

SsESoNn schu OME She ts y

M

X/

Sodium carbonate (1 mmol, 138 mg) was added to a 0.2 M-DMF solution of the compound of Example 667 (500 μl, 100 μmol), and a 0.3 M-DMF solution (500 μl, 150 μmol) was added dropwise to the resulting solution. 1-(2) -bromethyl)-1H-pyrrolyl. The reaction mixture was stirred at 40°C overnight. Ethyl acetate (3 mL) and water (2 mL) were added to the mixture, and the mixture was extracted and the organic layer was separated.

Ethyl acetate was evaporated under reduced pressure and the residue was dissolved in acetonitrile (500 μL), purified (trifluoroacetic acid type) by preparative HPLC to give the title compound. yield: 6.9 mg

LC-MS analysis: degree of purity 84 95

MS (EBIyayu): 495 (MAN)

Example 595 - Example 602

By a procedure similar to that of Example 594, the compounds listed in Table 1 were prepared from the compound of Example 667 or Example 683 and the corresponding halide.

Table 1

An example of Mo | structure output (mg) degree | Mo (EVIU) ! | purity (95)

Vetttnniah: - zones cm PP and fields - 4. 595 ME 100 498 yr and i : g: pd o (597 yad | 47 I 400 498 SHHI

N in y

Me i z g B5ov gy (100 486 ! : v | N N y, rani y i uv all ve A | ! ! koh MO Mn Nyvy p vysh pnia

GB ut 74 100 vm SHI v ry N ist cr ! t tires only tires shi shi 600 | Shk STILL in |525

OV and that too! ; ry sedan N

I ov I | and

Maybe N

In ShY et zi | 97 558. : in the year Y and 1

Sho

SOM NV; vyya and their 7 7 nenya and pa U UCHI 602 7 183 100 Ba?

H What "I | !

In | an sejo, also N

Example 603

Production of ethyl (2-C1-(hydroxyacetyl)piperidin-4-yl|carbamoyl)-3-methoxy-1-methyl-4-oxo-1,4-dihydro-5H-pyrrolo|3,2-c|quinoline-5 -yl) uaacetate c) OH

M cheeks,

M

Me, N

ХЕ ху ОМе

I SHKF) o - SE.SON

ABOUT

Sodium carbonate (1 mmol, 138 mg) was added to a 0.2M-DMF solution of the compound of Example 672 (500 μl, 100 μmol), and a 2M-OME solution (500 μl, 1 mmol) of ethyl bromoacetate was added dropwise to the resulting solution. The reaction mixture was stirred at 80°C overnight. After completion of the reaction, DMF was evaporated using a centrifugal vacuum concentrator while heating at 60°C. Acetonitrile-DMSO (1:11, 500 μl) was added to the residue and the insoluble material was filtered off. The filtrate was purified (ammonium carbonate type) by preparative HPLC to afford the title compound. yield: 2.9 mg

LC-MS analysis: degree of purity 97 Fo

MC(EZI I): 499 (MAN)

Example 604 - Example 618

By a procedure similar to that of Example 594, the compounds shown in Table 2 were prepared from the compound of Example 672 and the corresponding halide.

Table 2

Example Me structure output (mMg) o degree of me (EV . purity (95) ron p ponaanii 6o4 | and 7.3 | 100 499 ! | we and

Gweshi

I ! g 605 | in 84 | 100 | For? ! NO, and I also know that they are a student of Pushinnnna's wife zu in v2 7 p 452 rem ; ol | and N rt rn tt 607 | 768 (100 468 I SYA, me - | in 132 100 4vo o knocked | And sko and | : і vo ne 107 tob (469 more Ko blows ! and write shi vo | uko cho and sht shi

And ev zi

E ned :::

and i re pe | And here I am | 547 ш nosha tlu 5 I and pay,

AI

"shiny shi mes | yy yy shsh od | 9 -

E rod Z o i: not she

A 7 shk shk C | " oo : i- | she N E 615: uadenya 4 o 5.3 pi chi | i : me u SHHI ho sfe sko | sh av what

What's more, and | 100 - re | | 83

Sho | IN

And in 17 penni ninnsinnnya shi chni am sn still and | | 10 things about wasps | | and

In z: ni ni shi shi

E and EB led | Don't live at 100,495! | neni N i N ore | ' tires in Tynynyishshsh

Example 619

Preparation of 3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-M-(1-pyridin-3-ylpiperidin-4-yl)-4,5-dihydro-1H-pyrrolyl3 ,2-c|quinoline-2-carboxamide

What,

M

Me N

X xx OMe

I. M is, h

By a procedure similar to that of Example 575, the title compound (19 mg, 5.4 95) was obtained as a white solid from the compound of Auxiliary Example 77 (300 mg, 0.64 mmol) and 3-bromopyridine ( 0.50 ml, 5.2 mmol). "H-NMR (300 MHz, DMSO-av) 6: 1.58-1.81 (2H, m), 1.89-2.04 (2H, m), 2.90-3.04 (2H, m), 3.64-3.77 (2Н, m), 3.97 (ЗН, с), 4.00-4.13 (1Н, m), 4.32 (ЗН, с), 5.97 (2Н, с), 7.15-7.25 (1Н, m), 7.27-7.41 (ЗН, m), 7.42-7.52 (IN, m), 7.57-7 .68 (2H, m), 7.71-7.82 (1H, m), 7.93-8.04 (2H, m), 8.11-8.21 (2H, m), 8.30 -8.43 (2H, m).

Example 620

Preparation of 3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-N-(1-pyridin-2-ylpiperidin-4-yl)-4,5-dihydro-1H-pyrrolyl3 ,2-s|quinoline-2-carboxamide uh -M

M cheeks,

M

Me, N

X xx OMe

I, ICF) x

A solution of the compound of Example 77 (284 mg, 0.60 mmol), 2-iodopyridine (0.13 mL, 1.2 mmol) and potassium carbonate (208 mg, 1.5 mmol) in DMF (3.0 mL) was stirred at 90 °C for 5.5 h. 2-Bromopyridine (0.23 mL, 2.5 mmol) and triethylamine (0.49 mL, 3.5 mmol) were added to the reaction mixture, and the mixture was stirred under microwave radiation at 165 °C. C for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on amino silica gel (eluate; ethyl acetate/hexane-30/70-100/0) and recrystallized from THF-diethyl ether to give the title compound (38 mg, 12 95) as a white solid. "H-NMR (300 MHz, DMSO-α) 6: 1.45-1.65 (2H, m), 1.86-2.00 (2H, m), 2.99-3.14 (2H, m), 3.95 (ЗН, с), 4.03-4.14 (1Н, m), 4.16-4.26 (2Н, m), 4.31 (ЗН, с), 5.97 (2H, s), 6.61 (1H, dd, 9U-6.8, 5.1 Gu), 6.87 (1H, d, 928.7 Hz), 7.26-7.42 (2H, m), 7.43-7.57 (2H, m), 7.59-7.68 (2H, m), 7.70-7.81 (1H, m), 7.97 (1H, d, U-7.9 Hu), 8.08-8.21 (ZH, m), 8.37 (1H, d, 9-:7.7 Hz).

Example 621

Preparation //- M-/1-(2-cyanophenyl)piperidin-4-yl|-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro -1H-pyrrolo|3,2-c|quinoline-2-carboxamide

M SM shk,

X xx OMe and ICF) i

A solution of the compound of Example 77 (300 mg, 0.59 mmol), 2-fluorobenzonitrile (0.50 mL, 4.6 mmol) and triethylamine (0.50 mL, 3.6 mmol) in DMF (3.5 mL) was stirred under microwave radiation at 130 "C for 30 minutes. 2-Bromobenzonitrile (143 mg, 1.2 mmol) and potassium carbonate (208 mg, 1.5 mmol) were added to the reaction mixture, and the mixture was stirred under microwave radiation at 165 "C within 30 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by amino silica gel chromatography (eluate; ethyl acetate/hexane-50/50-100/0) and recrystallized from ethyl acetate-hexane to give the title compound (74 mg, 22,905) as a pale yellow solid. "H-NMR (300 MHz, DMSO-α) 5: 1.72-1.89 (2H, m), 1.97-2.10 (2H, m), 2.94-3.08 (2H, m), 3.43-3.54 (2H, m), 3.95-4.14 (AN, m), 4.32 (ZH, s), 5.98 (2H, s), 7.05 -7.13 (1H, m), 7.22 (1H, d, 9-81 Gu), 7.28-7.42 (2H, m), 7.44-7.52 (1H, m), 7.56-7.81 (5H, m), 8.06 (IN, d, 9U-7.9 Hz), 8.14-8.23 (2H, m), 8.38 (1H, dd, U-8,3,1,1 Gu).

Example 622

Preparation of /- M-/1-(3Z-cyanophenyl)piperidin-4-yl|-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro- 1H-pyrrolo|Z,2-c|quinoline-2g-carboxamides

Su"

M sh,

M

Me, Ts

H

HU OMe

And Sho) and

A solution of the compound of Example 77 (300 mg, 0.59 mmol), 3-bromobenzonitrile (143 mg, 1.2 mmol), tricydibenzylideneacetone)idipalladium (0) (54 mg, 0.059 mmol), x-rpo5 (56 mg, 0, 12 mmol), sodium tert-butoxide (142 mg, 1.5 mmol) and triethylamine (0.082 mL, 0.59 mmol) in 2-butanone (4.0 mL) were stirred under microwave radiation at 130 "C for 40 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on amino silica gel (eluate; ethyl acetate/hexane-40/60-100/0) and recrystallized from ethyl acetate-hexane to give the indicated in the title compound (25 mg, 7.4 95) as a white solid. "H-NMR (300 MHz, DMSO- av) 6: 1.58-1.74 (2H, m), 1.88- 2.01 (2H, m), 2.94-3.07 (2H, m), 3.71-3.83 (2H, m), 3.96 (ZH, s), 4.00-4, 12 (1Н, m), 4.31 (ЗН, с), 5.97 (2Н, с), 7.10-7.16 (1Н, m), 7.27-7.42 (5Н, m) , 7.44-7.52 (IN, m), 7.58-7.68 (2Н, m), 7.71-7.80 (1Н, m), 7.99 (1H, d, 9-7.9 Hu), 8.11-8.22 (2H, m), 8.38 (1H, dd, 9U-8.3, 11 Hu.

Example 623

Preparation of 3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-M-11-(2-trifluoromethyl)pyridin-4-yl|Ipiperidin-4-yl)-4, 5-dihydro-1H-pyrrolo|3,2-s|quinoline-2-carboxamide

M

M sh,

M

Me, y

X xx OMe

And MF) i

A solution of the compound of Example 77 (300 mg, 0.59 mmol), potassium carbonate (204 mg, 1.5 mmol) and triethylamine (0.082 ml, 0.59 mmol) in DMF (3.0 ml) was heated to 80 °C, 4-bromo-2-(trifluoromethyl)pyridine (133 mg, 0.59 mmol) was added and the mixture was stirred at 100 °C for 23 hours.

The reaction mixture was diluted with water and extracted three times with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on amino silica gel (eluate; ethyl acetate/hexane-50/50-100/0) and recrystallized from ethyl acetate-hexane to give the title compound (126 mg, 35 95) as a white solid. "H-NMR (300 MHz, DMSO-av) 6: 1.52-1.70 (2H, m), 1.89-2.02 (2H, m), 3.11-3.25 (2H, m), 3.90-4.07 (BN,

m), 4.10-4.24 (1H, m), 4.31 (ZH, s), 5.97 (2H, s), 7.08 (1TN, dd, 9U-6.1, 2, 5 Hz), 7.21-7.27 (1H, m), 7.27-7.41 (2H, m), 7.43-7.52 (1H, m), 7.57-7.67 (2H, m), 7.72-7.80 (1H, m), 7.98 (1H, d, 9U-7.9 Hz), 8.13-8.21 (2H, m), 8, 27 (1H, d, 9U-5.9 Hz), 8.37 (1H, dd, U-8.2, 1.2 Hz).

Example 624

Preparation of M-(1-(2-cyanopyridin-4-yl)piperidin-4-yl|-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5- dihydro-1H-pyrrolo|3,2-s|quinoline-2-carboxamide

M

M

Me, and

X х ОМе

And M is); and

By a procedure similar to that of Example 623, the title compound (70 mg, 21 95) was obtained as a white solid from the compound of Example 77 (300 mg, 0.59 mmol) and 4-iodopyridine-2-carbonitrile (136 mg, 0.59 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.50-1.69 (2H, m), 1.86-1.98 (2H, m), 3.10-3.25 (2H, m), 3.90-4.05 (5Н, m), 4.08-4.24 (1Н, m), 4.31 (ЗН, с), 5.97 (2Н, с), 7.10 (1H, dd, 9-61, 2.7 Hu), 7.25-7.42 (2H, m), 7.43-7.55 (2H, m), 7.58-7.68 (2H , m), 7.71-7.80 (1Н, m), 7.97 (1Н, d, 957.7 Gu), 8.11-8.27 (ЗН, m), 8.37 (1Н, dd, 9U-8,3, 11 Gu.

Example 625

Preparation of M-I(4-(hydroxymethyl)cyclohexyl|-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrroloyi3,2-s |quinoline-2-carboxamide on

M

Me, y

X with OMe and ShKF) i

By a procedure similar to that of Example 25, the title compound (165 mg, 64 95) was obtained as a white solid from the compound of Auxiliary Example 28 (200 mg, 0.51 mmol) and (4-aminocyclohexyl)methanol ( 130 mg, 1.0 mmol). "H-NMR (300 MHz, DMSO-α) 6: 0.92-1.10 (2H, m), 1.21-1.43 (ZH, m), 1.72-1.86 (2H, m), 1.89-2.02 (2Н,

M), 3.24 (2H, t, U-5.8 Hu), 3.66-3.83 (1H, m), 3.96 (ZH, s), 4.31 (ZH, s), 4.42 (1H, t, 9U-5.3 Gu), 5.97 (2H, s), 7.25-1.41 (2H, m), 7.42-7.53 (1H, m) , 7.58-7.68 (2H, m), 7.71-7.85 (2H, m), 8.10-8.22 (2H, m), 8.37 (1H, dd, 3- 8,3,11 Gu).

Example 626

Preparation of M-(1-(6-cyanopyridin-3-yl)piperidin-4-yl|-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-

phenylethyl)-4,5-dihydro-1H-pyrrolo|3,2-s|quinoline-2-carboxamide

SM

; their

M shk,

M

Me Y

X xx OMe

MF) x

By a procedure similar to that of Example 623, the title compound (52 mg, 15 95) was prepared as a pale yellow solid from the compound of Example 77 (300 mg, 0.59 mmol) and 5-bromopyridine-2 -carbonitrile (119 mg, 0.65 mmol). "H-NMR (300 MHz, DMSO-av) 6: 1.56-1.74 (2H, m), 1.88-2.02 (2H, m), 3.10-3.25 (2H, m), 3.91-4.04 (BN, m), 4.06-4.22 (1Н, m), 4.31 (ЗН, с), 5.97 (2Н, с), 7.25 -7.52 (AN, m), 7.58-7.68 (2H, m), 7.71-7.81 (2H, m), 7.98 (IN, d, U-7.9 Gu ), 8.12-8.21 (2H, m), 8.37 (1H, dd, U-8.3, 1.1 Hz), 8.46 (1H, d, 9U-2.8 Hz) .

Example 627

Preparation of M-P1-(hydroxyacetyl)piperidin-4-yl|-3-methoxy-1-methyl-5-|(b-methylpyridin-2-ylmethyl|-4-oxo-4,5-dihydro-1H-pyrrolo |3,2-c) quinoline-2-carboxamide 6) on

M cheeks,

M

Me, Y

X s OMe she)

M. Meche -

According to a method similar to the method given in Example 570, 2-A4-(((3-methoxy-1-methyl-5-|(6-methylpyridin-2-yl)methyl|-4-oxo-4,5-dihydro -1H-pyrrolo|3,2-c)quinoline-2-ylcarbonyl)amino|piperidin-1-yl)y-2-oxoethyl acetate (80 mg) was obtained as a colorless amorphous solid from the compound

Example 672 (300 mg, 0.66 mmol), 2-(chloromethyl)-6b-methylpyridine hydrochloride (940 mg, 5.28 mmol) and cesium carbonate (2.18 g, 6.60 mmol).

Solution of /2-14-((3-methoxy-1-methyl-5-|(6b-methylpyridin-2-ylylmethyl|-4-oxo-4,5-dihydro-1H-pyrroloi|3,2- sequinoline-2 -ylcarbonyl)amino|piperidin-1-yl)y-2-oxoethyl acetate (80 mg) and potassium carbonate (100 mg, 0.71 mmol) in THF (2 mL)-methanol (1 mL)-water (1 mL) stirred at room temperature for 3 hours. The reaction mixture was diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from 3 ethyl acetate-hexane to give the title compound (37 mg , 11 95) in the form of white crystals. "H-NMR (300 MHz, DMSO-α) 6: 1.40-1.60 (2H, m), 1.90 (2H, d, 9U-9.6 Hz ), 2.47 (ZH, s), 2.93 (1H, t,

9U-11.7 Gu), 3.14 (1TN, t, 9U-11.6 Gu), 3.67 (1H, d, U-12.9 Hz), 3.99-4.29 (TON, m), 4.52 (1H, t, U-5.4 Hz), 5.59 (2H, s), 6.71 (IN, d, U-7.8 Hz), 7.12 (1H, d, 9U-7.8 Hz), 7.29 (1H, t, 9U-7.5 Gu), 7.37-7.48 (2H, m), 7.55 (1H, t, 9U-7 .8 Hz), 7.98 (1H, d, U9-7.8 Hz), 8.35 (1H, d, 9U-7.2 Hz).

Example 628

Preparation // 5-(2-chlorobenzyl)-M-(1-(hydroxyacetyl)piperidin-4-yl|-3-methoxy-1-methyl-4-oxo-4,5- dihydro-1H-pyrroloyi3,2- c|quinoline-2-carboxamide (6) on

M

IN,

M

Me Y

X xx OMe

M (6)

In -

According to a method similar to the method given in Example 570, 2-(4-(15-(2-chlorobenzyl)-3-methoxy-1-methyl-4-oxo-4,5-dihydro-1H-pyrrole|3, 2-C|quinoline-2-ylcarbonyl)amino)piperidine-1-yl|-2-oxoethyl acetate (80 mg) was obtained as a colorless amorphous solid from the compound

Example 672 (300 mg, 0.66 mmol), 2-chlorobenzyl chloride (1.06 g, 6.60 mmol) and cesium carbonate (2.18 g, 6.60 mmol).

Solution 2-I4-(15-(2-chlorobenzyl)-3-methoxy-1-methyl-4-oxo-4,5-dihydro-1H-pyrrolo|3,2-c)quinolin-2-yl|carbonyl )amino)piperidin-1-yl|-2-oxoethyl acetate (80 mg) and potassium carbonate (100 mg, 0.71 mmol) in

THF (2 mL)-methanol (1 mL)-water (1 mL) was stirred at room temperature for 3 hours.

The reaction mixture was diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate.

The extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (8 mg, 2 95) as white crystals. "H-NMR (300 MHz, DMSO-α) 6: 1.40-1.60 (2H, m), 1.90 (2H, d, 9U-12.3 Hz), 2.93 (1H, t , U-11.0 Hu), 3.15 (IN, t, 9U-11.6 Hu), 3.68 (1Н, d, U-13.5 Hz), 3.99-4.34 (1ОН , m), 4.52 (1H, t, U-5.4 Gu), 5.58 (2H, s), 6.59 (1H, d, 9-7.5 Hz), 7.14-7 .20 (2H, m), 7.27-7.34 (2H, m), 7.47 (1H, t, U-7.8 Hz), 7.57 (1TN, d, 9U-8.1 Hz), 7.99 (IN, d,

U-7.8 Hz), 8.39 (1H, d, U-8.4 Hz).

Example 629

Preparation of M-P1-«(hydroxyacetyl)piperidin-4-yl|-3-methoxy-1-methyl-5-C2-methyl-6-(trifluoromethyl)pyridin-3-yl|methyl)-4-oxo-4, 5-dihydro-1H-pyrrole|3,2-s|quinoline-2-carboxamide vch

M cheeks,

M

Me, Y

X xx OMe

M (6) сх - E

Me ME

IS

According to a method similar to the method given in Example 570, 2-(4-1(3-methoxy-1-methyl-5-Ce-methyl-6-(trifluoromethyl)pyridin-3-yl|methyl)-4-oxo- 4,5-Dihydro-1H-pyrrole|3,2-c)quinolin-2-yl)ucarbonylamino)piperidin-1-yl)-2-oxoethyl acetate (50 mg) was obtained as a colorless amorphous solid from the compound of Example 672 (300 mg, 0.66 mmol), 3-chloromethyl-2-methyl-6-trifluoromethylpyridine (980 mg, 4.68 mmol) and cesium carbonate (1.09 g, 3.30 mmol).

A solution of 2-(4-C(3-methoxy-1-methyl-5-C2-methyl-6-trifluoromethyl)pyridin-3-yl|methyl)-4-oxo-4,5-dihydro-1H-pyrrolyl3, of 2-si|quinolin-2-yl(ucarbonylamino)piperidin-1-yl)-2-oxoethyl acetate (50 2 mg) and potassium carbonate (55 mg, 0.40 mmol) in THF (2 mL)-methanol (1 mL )-water (1 ml) was stirred at room temperature for 3 hours. The reaction mixture was diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate. The extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (19 mg, 5,905) as white crystals. "H-NMR (300 MHz, DMSO-dv) 6: 1.40-1.60 (2H, m), 1.89 (2H, d, 9U-13.5 Hz), 2.77 (ZH, s ), 2.92 (1H, t, 3U-9.9 Hz), 3.14 (1IN, t, 9U-11.4 Gu), 3.68 (IN, d, 9U-12.9 Hz), 3.98 (ZH, s), 4.00-4.33 (7H, m), 4.52 (1H, t, y-5.4 Hu), 5.62 (2H, s), 6.99 (1H, d, 9-7.8 Hz), 7.29-7.36 (2H, m), 7.47 (1H, t, U-7.5 Hz), 7.54 (1H, d, 9-81

Hz), 7.99 (TN, d, 9U-7.5 Hz), 8.40 (1H, d, U-6.9 Hz).

Example 630

Production // 5-(4-chlorobenzyl)-M-(1-(hydroxyacetyl)piperidin-4-yl|-3-methoxy-1-methyl-4-oxo-4,5- dihydro-1H-pyrroloyi3,2- c|quinoline-2-carboxamide c) on

M shk,

X xx OMe

I. M is) cen

According to a method similar to the method given in Example 570, 2-(4-(15-(4-chlorobenzyl)-3-methoxy-1-methyl-4-oxo-4,5-dihydro-1H-pyrrole|3, 2-C|quinoline-2-ylcarbonyl)amino)piperidine-1-yl|-2-oxoethyl acetate (60 mg) was obtained as a white solid from the compound of Example 672 (200 mg, 0.44 mmol), 4-chlorobenzyl chloride (708 mg, 4.40 mmol) and cesium carbonate (572 g, 1.76 mmol).

Solution 2-I4-(15-(4-chlorobenzyl)-3-methoxy-1-methyl-4-oxo-4,5-dihydro-1H-pyrrolo|3,2-c)quinolin-2-yl|carbonyl )iamino)piperidin-1-yl|-2-oxoethyl acetate (60 mg) and potassium carbonate (72 mg, 0.52 mmol) in

THF (2 mL)-methanol (1 mL)-water (1 mL) was stirred at room temperature for 3 hours.

The reaction mixture was diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate.

The extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (7 mg, 2 95) as white crystals. "H-NMR (300 MHz, DMSO-α) 6: 1.40-1.60 (2H, m), 1.90 (2H, d, 9U-10.8 Hz), 2.93 (1H, t , U-12.0 Hu), 3.15 (IN, t, U-12.0 Hu), 3.68 (1H, d, 9U-13.5 Hz), 4.01-4.34 (TON , m), 4.52 (1H, t, 9-5.4 Gu), 5.59 (2H, w s), 7.20-7.49 (7H, m), 7.99 (1H, d , U-5.4 Hz), 8.35 (1H, d, U-8.1 Gu).

Example 631

Preparation of M-(1-(2-carbamoylpyridin-4-yl)/piperidin-4-yl|-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5 -dihydro-1H-pyrrolo|3,2-s|quinoline-2-carboxamide

M (6) / x - MH,

M sh,

M

Me and

H

HU OMe

And SHKF) and

By a procedure similar to that of Example 623, the title compound (58 mg, 17 95) was prepared as a pale red solid from the compound of Example 77 (300 mg, 0.59 mmol) and 4-bromopyridine-2 -carboxamide (119 mg, 0.59 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.52-1.72 (2H, m), 1.88-2.05 (2H, m), 3.07-3.24 (2H, m), 3.86-4.03 (5Н, m), 4.07-4.22 (1Н, m), 4.31 (ЗН, с), 5.96 (2Н, с), 6.93 -7.08 (1Н, m), 7.25-7.41 (2Н, m), 7.43-7.54 (ЗН, m), 7.56-7.68 (2Н, m), 7 ,70-7.82 (1H, m), 7.91-8.04 (2H, m), 8.10-8.25 (ZH, m), 8.37 (1H, dd, U-8, 3, 1.1 Hz).

Example 632

Preparation of 3-methoxy-IM-(1-(2-methoxypyridin-4-yl)piperidin-4-yl|-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5- dihydro-1H-pyrrolo|3,2-s|quinoline-2-carboxamide

M

M sh,

M

Me, N

X xx OMe

And ICF) and

By a procedure similar to that of Example 575, the title compound (51 mg, 15 95) was obtained as a white solid from the compound of Example 77 (300 mg, 0.59 mmol) and 4-bromo-2-methoxypyridine (122 mg, 0.65 mmol). "H-NMR (300 MHz, DMSO-α) 5: 1.49-1.70 (2H, m), 1.85-2.00 (2H, m), 2.98-3.12 (2H, m), 3.73-3.88 (5Н, m), 3.95 (ЗН, с), 4.03-4.18 (1Н, m), 4.31 (ЗН, с), 5.97 (2H, s), 6.15 (1H, d, U-2.3 Hz), 6.59 (1H, dd, 9-62, 2.3

Hz), 7.26-7.41 (2H, m), 7.43-7.52 (1H, m), 7.57-7.68 (2H, m), 7.71-7.84 ( 2H, m), 7.96 (1H, d, 9U-7.9 Hz), 8.09- 8.23 (2H, m), 8.37 (1H, dd, 9U-8.3, 1, 1 Hz).

Example 633

Preparation of 3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-M-11-16-"trifluoromethyl)pyridin-3-yl|Ipiperidin-4-yl)-4,5 -dihydro-1H-pyrrolo|3,2-s|quinoline-2-carboxamide

SE, ih ; m

M cheeks,

M

Me Y

Ххх ОМе i, ше) х

By a procedure similar to that of Example 623, the title compound (51 mg, 14 95) was prepared as a pale yellow solid from the compound of Example 77 (300 mg, 0.59 mmol) and 5-bromo-2 -(trifluoromethyl)pyridine (147 mg, 0.65 mmol). "H-NMR (300 MHz, DMSO- av) 6: 1.59-1.77 (2H, m), 1.91-2.02 (2H, m), 3.07-3.20 (2H, m), 3.86-4.00 (BN, m), 4.05-4.20 (1Н, m), 4.31 (ЗН, с), 5.97 (2Н, с), 7.27 -7.А1 (2Н, m), 7.43-7.52 (2Н, m), 7.58-7.67 (ЗН, m), 7.712-7.80 (IN, m), 7.98 (1H, d, 9U-7.9 Hz), 8.13-8.20 (2H, m), 8.37 (1H, dd, 9U-8.2, 1.0 Gu), 8.46 ( 1H, d, 9U-2.8

Gu).

Example 634

Preparation of 3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-M-11-(2-(trifluoromethyl)pyrimidin-4-yl|Ipiperidin-4-yl)-4, 5-dihydro-1H-pyrrolo|3,2-s|quinoline-2-carboxamide

M

/ U-se, -M

M what

M ke N x xx OMe

I. shk c) x

By a procedure similar to that of Example 623, the title compound (210 mg, 58 95) was obtained as a pale red solid from the compound of Example 77 (300 mg, 0.59 mmol) and 4-chloro-2 -«-«trifluoromethyl)pyrimidine (129 mg, 0.71 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.48-1.69 (2H, m), 1.91-2.07 (2H, m), 3.17-3.30 (2H, m), 3.96 (ZH, s), 4.10-4.52 (6Н, m), 5.97 (2Н, s), 7.12 (1Н, d, U-6.4 Hu), 7.26-7.41 (2H, m), 7.43-7.52 (1H, m), 7.57-7.68 (2H, m), 7.71-7.81 (1H, m ), 7.97 (1H, d, 9U-7.9 Hz), 8.11-8.22 (2H, m), 8.27-8.45 (2H, m).

Example 635

Preparation of 3-methoxy-1-methyl-N-11-(2-(methylcarbamoyl)pyridin-4-yl|piperidin-4-yl)-4-oxo-5-(2-oxo-2-phenylethyl)-4, 5-dihydro-1H-pyrrolo|3,2-s|quinoline-2-carboxamide

M (F) / xX - M-Me

M. N

M

Me, J

X with OMe

And M is) and

To a solution of 4-chloropyridine-2-carboxylic acid (200 mg, 1.3 mmol), methylamine hydrochloride (103 mg, 1.5 mmol), NOVI (205 mg, 1.5 mmol) and triethylamine (0.42 ml, 3.0 mmol) in DMF (3.0 mL) was added

MIZSO (292 mg, 1.5 mmol) while cooling on ice and the mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate. The extracts were combined, washed with saturated saline, dried over magnesium sulfate, filtered through amino silica gel, and the filtrate was concentrated under reduced pressure. The residue was dissolved in DMF (3.0 mL), the compound of Example 77 (300 mg, 0.59 mmol), potassium carbonate (204 mg, 1.5 mmol) and triethylamine (0.082 mL, 0.59 mmol) were added, and the mixture stirred at 100 C for 16 hours. The reaction mixture was diluted with a saturated solution of sodium bicarbonate and extracted twice using a solvent mixture of ethyl acetate-THF.

The extract was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on amino silica gel (eluate; ethyl acetate/hexane-40/60-100/0) and recrystallized from ethyl acetate-hexane to give the title compound (40 mg, 11 95) as a pale yellow solid. "H-NMR (300 MHz, DMSO-dv) 5: 1.52-1.72 (2H, m), 1.90-2.05 (2H, m), 2.79 (ZH, d, U- 4.9 Hz), 3.09-3.22 (2H, m), 3.88-4.02 (5H, m), 4.07-4.22 (1H, m), 4.31 (ZH , s), 5.96 (2H, s), 7.01 (1H, dd, 9U-6.0, 2.68 Hz), 7.25- 7T,A1 (2H, m), 7.43- 7.52 (2H, m), 7.57-7.68 (2H, m), 7.70-7.81 (1H, m), 7.98 (1H, d, 9U-7.9 Hz) , 8.11-8.24 (ZH, m), 8.37 (1H, dd, yU-8.3, 1.1 Gu), 8.53-8.70 (1H, m).

Example 636

Preparation of M-P1-"hydroxyacetyl)-3-methylpiperidin-4-yl|-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H- pyrrolo|3,2-c|quinoline-2-carboxamide ) on b i;

M Me

Me Ts

X xx OMe and MF) i

By a procedure similar to that of Example 130, the title compound (21 mg, 22 95) was obtained as a white solid from the compound of Example 678 (83 mg, 0.17 mmol). "H-NMR (300 MHz, DMSO- av) 6: 0.82-1.02 (ZN, m), 1.55-2.40 (ZN, m), 3.14-3.77 (AN, m), 3.93-4.05 (ZN,

m), 4.07-4.17 (2Н, m), 4.20-4.41 (4Н, m), 4.45-4.57 (1Н, m), 5.98 (2Н, s) , 7.25-7.42 (2H, m), 7.43-7.53 (1H, m), 7.58-7.68 (2H, m), 7.71-7.80 (1H, m), 7.85-8.05 (1H, m), 8.10-8.24 (2H, m), 8.38 (1H, dd, 9U-8.4, 1.2 Hz).

Example 637

Preparation of 3-methoxy-1-methyl-N-(1-(2-methylpyrimidin-4-yl)piperidin-4-yl|-4-oxo-5-(2-oxo-2-phenylethyl)-4,5- dihydro-1H-pyrrolo|3,2-s|quinoline-2-carboxamide

M

/ U-me -M

M n,

Mke N

X xx OMe

I. M c) x

By a procedure similar to that of Example 623, the title compound (130 mg, 59 95) was obtained as a pale brown solid from the compound of Example 77 (200 mg, 0.39 mmol) and 4-chloro-2 -methylpyrimidine (61 mg, 0.47 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.44-1.62 (2H, m), 1.85-2.01 (2H, m), 2.36 (ZH, s), 3 ,06-3.23 (2Н, m), 3.96 (ЗН, с), 4.06-4.23 (1Н, m), 4.24-4.41 (5Н, m), 5.97 (2H, s), 6.68 (1H, d, 9U-6.4 Hz), 7.25-7.42 (2H, m), 7.43-7.53 (1H, m), 7, 57-7.69 (2H, m), 7.71-7.82 (1H, m), 7.96 (1H, d, 9-7.9 Hz), 8.08 (1H, d, 9U- 6.2 Hz), 8.13-8.22 (2H, m), 8.37 (1TN, d, 9U-7.6 Hz).

Example 638

Preparation of 3-methoxy-1-methyl-N-(/1-(6-methylpyrimidin-4-yl)piperidin-4-yl|-4-oxo-5-(2-oxo-2-phenylethyl)-4,5 -dihydro-1H-pyrrolo|3,2-s|quinoline-2-carboxamide

Me

M v, -M

M cheeks,

M

Me, Y

X with OMe and ICF) zh

By a procedure similar to that of Example 623, the title compound (137 mg, 62 95) was prepared as a pale brown solid from the compound of Example 77 (200 mg, 0.39 mmol) and 4-chloro-6 -methylpyrimidine (61 mg, 0.47 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.44-1.64 (2H, m), 1.85-2.01 (2H, m), 2.26 (ZH, s), 3 .05-3.23 (2Н, m), 3.95 (ЗН, с), 4.07-4.23 (1Н, m), 4.24-4.39 (5Н, m), 5.97 (2H, s), 6.77 (1H, s), 7.25-7.42 (2H, m), 7.43-7.53

(IN, m), 7.57-7.69 (2H, m), 7.70-7.82 (1H, m), 7.96 (1H, d, 9-7.9 Hz), 8, 11-8.23 (2H, m), 8.32-8.45 (2H, m).

Example 639

Preparation of /- 1-ethyl-M-(1-(hydroxyacetyl)piperidin-4-yl|-3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H- pyrrolo|3,2-s|quinoline-2-carboxamide ) on

M

M also

X xx OMe

And M is) and

By a procedure similar to that of Example 140, the title compound (42 mg, 22 95) was obtained as a white solid from the compound of Auxiliary Example 120 (140 mg, 0.35 mmol) and 2-(4-aminopiperidine) -1-yl)-2-oxoethanol hydrochloride (81 mg, 0.42 mmol). "H-NMR (300 MHz, DMSO-av) 6: 1.39-1.61 (5Н, m), 1.82-1.98 (2Н, m), 2.84-3.01 (1Н, m), 3.06-3.21 (1Н, m), 3.59-3.74 (1Н, m), 3.96 (ЗН, с), 4.03-4.14 (ЗН, m) , 4.16-4.28 (1H, m), 4.51 (1H, t, U-5.4 Hz), 4.82 (2H, k, uU7.1 Hz), 5.98 (2H, c), 7.30-7.42 (2Н, m), 7.43-7.52 (1Н, m), 7.59-7.68 (2Н, m), 7.71-7.81 ( 1Н, m), 8.03 (1Н, d, 9-7.7 Gu), 8.12-8.25 (ЗН, m).

Example 640

Preparation of M-(1-(hydroxyacetyl)azepan-4-yl|-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolyl3, 2-c|quinoline-2-carboxamide (in) "Zhk oon in)

M

Me and

X xx OMe

And M c) x

A mixture of a solution of the compound of Auxiliary Example 123 (220 mg, 0.70 mmol) and an 8M aqueous solution of sodium hydroxide (0.36 ml) in ethanol (3.0 ml)-water (3.0 ml) was stirred for 30 minutes while cooling at ice The reaction mixture was neutralized with TM hydrochloric acid, stirred for 10 minutes while cooling on ice and extracted twice with ethyl acetate. The extracts were combined, washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (2.0 ml) and a 4M solution of hydrochloride in ethyl acetate (2.0 ml) was added. The mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. To a solution of the residue, the compound of Auxiliary Example 28 (200 mg, 0.51 mmol), NOVI (90 mg, 0.67 mol) and triethylamine (0.22 mL, 1.6 mmol) in DMF (5.0 mL) was added M/5CO (128 mg, 0.67 mmol) while cooling on ice, and the mixture was stirred at room temperature for 62 hours. The reaction mixture was diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate. The extracts were combined, washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on amino silica gel (eluate; ethyl acetate/hexane-80/20-100/0) and recrystallized from THF-diethyl ether to give the title compound (122 mg, 44 90) as a white solid. "H-NMR (300 MHz, DMSO-α) 6: 1.55-1.92 (5Н, m), 1.93-2.11 (1Н, m), 3.25-3.45 (2Н, m), 3.47-3.55 (1Н, m), 3.63-3.80 (1Н, m), 3.92-4.06 (4Н, m), 4.07-4.18 ( 2H, m), 4.25-4.36 (ZH, m), 4.43 (1H, t, 9U-4.7 Hz), 5.97 (2H, s), 7.24-7.42 (2H, m), 7.43-7.52 (1H, m), 7.58-7.67 (2H, m), 7.71-7.81 (1H, m), 7.94 (1H , d, 9-81 Gu), 8.12-8.22 (2H, m), 8.37 (1 H, d, 9-7.9 Hz).

Example 641

Preparation of M-/1-(2-hydroxyethyl)azepan-4-yl|-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H- pyrroloI3,2-c|quinoline-2-carboxamide mon that

X xx OMe

MF) i

A solution of the compound of Auxiliary Example 122 (157 mg, 0.73 mmol) and potassium carbonate (607 mg, 4.4 mmol) in DMF (6.0 ml) was stirred at 100 °C for 5 minutes, 2-bromomethanol was added to the reaction mixture (0.16 ml, 2.2 mmol) and the mixture was stirred at 100 "C for 1 hour. The reaction mixture was diluted with water, saturated saline was added, and the mixture was extracted 4 times with ethyl acetate.

The extracts were combined, dried over magnesium sulfate and concentrated under reduced pressure.

The residue was purified by chromatography on amino silica gel (eluate; methanol/ethyl acetate-0/100-5/95). The residue was dissolved in ethyl acetate (2.0 ml) and a 4M solution of hydrochloride in ethyl acetate (2.0 ml) was added. The reaction mixture was stirred at room temperature for 30 minutes and concentrated under reduced pressure. To a solution of the residue, the compound of Auxiliary Example 28 (200 mg, 0.51 mmol) and triethylamine (0.27 mL, 1.9 mmol) in DMF (5.0 mL) was added OMT-MM (167 mg, 0.61 mmol) ) while cooling on ice and the mixture was stirred at room temperature for 62 hours. The reaction mixture was diluted with a saturated solution of sodium bicarbonate and water, and extracted with ethyl acetate.

The extracts were combined, washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on amino silica gel (eluate; ethyl acetate/hexane-50/50-100/0) and recrystallized from ethanol-hexane to give the title compound (75 mg, 28 95) as a pale yellow solid. "H-NMR (300 MHz, DMSO-av) 6: 1.49-2.01 (6Н, m), 2.53-2.84 (6Н, m), 3.44-3.56 (2Н, m), 3.90-4.03 (ЗН, m), 4.14-4.41 (5Н, m), 5.97 (2Н, с), 7.25-7.42 (2Н, m) , 7.43-7.53 (1 H, m), 7.57-7.69 (2H, m), 7.71-7.82 (1H, m), 8.04 (1H, d, 9U -8.3 Gu), 8.11-8.23 (2H, m), 8.37 (1H, dd, 9U-8.3, 1.1 Hz).

Example 642

Preparation of 2-K(4-aminopiperidin-1-yl)ucarbonyl|-3-methoxy-1-methyl-5-(2-oxo-2-phenylethyl)-1,5-dihydro-4H-pyrrolo|3,2- c|quinolin-4-one hydrochloride

Me Mo-t- no

M

X with OMe

M (6) x

By a procedure similar to that of Example 542, the title compound (119 mg, 79 95) was obtained as a white solid from the compound of Example 679 (170 mg, 0.30 mmol). "H-NMR (300 MHz, DMSO- av) 6: 1.36-1.73 (2H, m), 1.84-2.15 (2H, m), 2.83-3.04 (1H, m), 3.08-3.30 (2Н, m), 3.77-3.95 (АН, m), 4.00 (ЗН, с), 4.45-4.68 (1Н, m) , 5.98 (2Н, с), 7.24-7.52 (ЗН, m), 7.58-7.70 (2Н, m), 7.71-7.81 (1Н, m), 8 .00 (ZH, w s), 8.13-8.23 (2H, m), 8.33 (1H, dd, 9-82, 1.0 Gu).

Example 643

Preparation of M-/1-(hydroxyacetyl)piperidin-4-yl|-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo| 3,2-s|/1,8|Inaphthyridine-2-carboxamide 6) OH

M what

M

Me, N

Khaz OMe rya

M ikh M c) x

By a procedure similar to that of Example 141, the title compound (141 mg, 69 95) was obtained as a white solid from the compound of Auxiliary Example 131 (150 mg, 0.38 mmol). "H-NMR (300 MHz, DMSO-av) 6: 1.32-1.65 (2H, m), 1.81-1.97 (2H, m), 2.81-3.01 (1H, m), 3.04-3.22 (1Н, m), 3.63-3.74 (1Н, m), 3.98 (ЗН, с), 4.04-4.16 (ЗН, m) , 4.17-4.28 (1H, m), 4.32 (ZH, s), 4.51 (1H, t, U-5.4 Hu), 5.99 (2H, s), 7, 35 (1H, dd, 9U-8.1, 4.7 Hz), 7.54-7.68 (2H, m), 7.69-7.80 (1H, m), 8.00 (1H, d, 9U-7.9 Hz), 8.08-8.22 (2H, m), 8.44 (1H, dd, 9-4.7, 1.5 Hz), 8.73 (1TN, dd , 9U-8.3, 1.5 Hz).

Example 644

Preparation of M-/1-(hydroxyacetyl)piperidin-4-yl|-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo| Y3,2-c|/1 b|Inaphthyridine-2-carboxamide

) he

M sh,

M

Me, Ts

H me HU OMe and mo y

By a procedure similar to that of Example 141, the title compound (97 mg, 48 95) was obtained as a white solid from the compound of Sub-Example 139 (150 mg, 0.38 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.34-1.63 (2H, m), 1.79-1.97 (2H, m), 2.83-3.01 (1H, m), 3.05-3.22 (1Н, m), 3.59-3.74 (1Н, m), 3.95 (ЗН, с), 4.01-4.17 (ЗН, m) , 4.17-4.28 (1H, m), 4.35 (ZH, s), 4.50 (1H, t, U-5.4 Hu), 5.95 (2H, s), 7, 42 (1H, d, 9U-6.2 Gu), 7.57-7.69 (2H, m), 7.71-7.82 (1H, m), 7.99 (1H, d, 9- 7.7 Hu), 8.10-8.22 (2H, m), 8.48 (1H, d, U-6.0 Hu), 9.51 (1H, s).

Example 645

Preparation of M-(2-(diethylamino)ethyl|-3-ethoxy-M,b-dimethyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno]3,2-c|Ipyridine- 2-carboxamide hydrochloride and

M-E 6); ,NO-

M

Me

X zhk (o/sh

Me M O nNesiI h

To a solution of the compound of Example 146 (150 mg, 0.310 mmol) in ethyl acetate (20 mL) was added a 4M solution of hydrochloride in ethyl acetate (93.0 μL, 0.372 mmol). The mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate (30 mL) and ethanol (5 mL). Hexane (10 mL) was added and the mixture was stirred at room temperature for 15 hours. The resulting solid was collected by filtration and washed with ethyl acetate to give the title compound (90.0 mg, 56 g) as a white solid. "H-NMR (300 MHz, DMSO-α) 5: 1.10-1.35 (9H, m), 2.30 (ZN, s), 3.08 (ZN, s), 3.00-3 .40 (6H, m), 3.79 (2H, t, 9U-7.2 Hu), 4.08 (2H, k, U-7.0 Hu), 5.67 (2H, s), 6 .84 (1TN, d, 9-06 Gu), 7.62 (2Н, t, 9-7.5 Hz), 7.72-7.78 (IN, m), 8.10-8.13 ( 2H, m), 10.03 (1H, s).

Example 646

Preparation of 3-ethoxy-M-(4-hydroxycyclohexyl)-1,6-dimethyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolyl3,2-c|Ipyridine -2-carboxamide

HE is);

Me, M

M

X (Fi

Me I shF) i

By a procedure similar to that of Example 25, the title compound (106 mg, 60 95) was obtained as a white powder from the compound of Auxiliary Example 44 (140 mg, 0.380 mmol) and 4-aminocyclohexanol (53 mg, 0.456 mmol) . "H-NMR (300 MHz, DMSO-α) 5: 1.19-1.35 (7H, m), 1.86 (4H, d, 9-12.8 Hz), 2.27 (ZH, s ), 3.45 (IN, w s), 3.71 (IN, w s), 3.86 (ZH, s), 4.33 (2H, k, 9U-6.9 Gu), 4.56 (1H, d, 9U-4.3 Hz), 5.61 (2H, s), 6.57 (1H, s), 7.48-7.67 (ZH, m), 7.72 (IN, d, U-7.2 Hz), 8.10 (2H, d, 9-74 Gu).

Example 647

Preparation of 33-ethoxy-1,6-dimethyl-4-oxo-5-(2-oxo-2-phenylethyl)-N-(tetrahydrofuran-2-ylmethyl)-4,5-dihydro-1H-pyrrolo|3,2 -c|Ipyridine-2-carboxamide (c) o Y-

Me, M

M

X xx (Fi

Me Me Me

By a procedure similar to that of Example 25, the title compound (114 mg, 66 95) was obtained as a white powder from the compound of Auxiliary Example 35 (140 mg, 0.380 mmol) and 2-tetrahydrofurfurylamine (47 μl, 0.456 mmol) . "H-NMR (300 MHz, DMSO-α) 6: 1.29 (ZH, t, uU-6.8 Hz), 1.48-1.62 (1H, m), 1.78-1.99 (ZH, m), 2.28 (ZH, s), 3.41-3.52 (1H, m), 3.60-3.71 (IN, m), 3.75-3.84 (1H , m), 3.89 (ZH, s), 3.91-4.02 (2 H, m), 4.35 (2H, t,

U-7.0 Gu), 5.61 (2H, s), 6.59 (1H, s), 7.61 (2H, t, 9U-7 4 Hz), 7.73 (1H, m), 7.88 (1H, w s), 8.11 (2H, d, 9U-7.6

Gu).

Example 648

Preparation of 33-ethoxy-b-ethyl-N-(transo-4-hydroxycyclohexyl)-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo|3 ,2-s|Ipyridine-2-carboxamide on

Me, M

I'm ok

E and ShK are) x

By a procedure similar to that of Example 25, the title compound (76 mg, 79 95) was obtained as a white powder from the compound of Auxiliary Example 42 (77 mg, 0.20 mmol) and trans-4-aminocyclohexanol (28 mg , 0.24 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.18 (ZN, t, U-7.4 Hu), 1.22-1.36 (7Н, m), 1.75-1.96 (4H, m), 2.57 (2H, k, 9U7.3 Gu), 3.44 (1H, w s), 3.71 (IN, w s), 3.89 (ZH, s), 4 .32 (2H, k, 957.1 Gu), 4.57 (1H, d, U-4.2 Hz), 5.58 (2H, s), 6.48 (1H, s), 7.51 -7.66 (ZH, m), 7.67-7.78 (1H, m), 8.11 (2H, d, 9-7.2 Hz).

Example 649

Preparation of M-/1-(hydroxyacetyl)piperidin-4-yl|-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo| І3,2-с|/1 b|Inaphthyridine-2-carboxamide he also,

M

Me, Ts

X shkh o uk mebtm"oto S E g d

By a procedure similar to that of Example 140, the title compound (132 mg, 54 90) was obtained as white crystals from the compound of Auxiliary Example 50 (200 mg, 0.47 mmol) and 4-aminocyclohexanol (82 mg, 0 .71 mmol). "H-NMR (300 MHz, DMSO-av) 5: 1.25 (4H, t, U-9.6 Gu), 1.80-1.90 (4H, m), 2.29 (ZH, s ), 3.30-3.45 (1H, shu, 3.60-3.80 (1H, w), 3.83 (ZH, s), 4.57 (1H, t, U-4.5 Hz ), 5.06 (2H, k, U-9.3 Hz), 5.65 (2H, s), 6.64 (1H, s), 7.31 (IN, d, 9U-7.8 Hz ), 7.61 (1TN, t, 9U-7.5 Hz), 7.74 (1Н, t, 9У-7.5 Hz), 8.09-8.12 (2Н, m).

Example 650

Preparation of 3-ethoxy-6-ethyl-M-|1-(hydroxyacetyl)piperidin-4-yl|-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoY3,2-s| Ipyridine-2-carboxamide

(in)

M on

WHAT,

M z xx OEi

EI I. M is); p.

By a method similar to the method given in Auxiliary Example 7, 3-ethoxy-b-ethyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno|3,2-c|Ipyridine -2-Carboxylic acid (700 mg, 83 95) was obtained as a purple powder from the compound of Auxiliary Example 170 (900 mg, 2.25 mmol). From the thus obtained 3-ethoxy-6-ethyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoic|3,2-sipyridine-2-carboxylic acid (550 mg, 1, 4 mmol) and 4-amino-1-Bos-piperidine (361 mg, 1.8 mmol) gave tert-Butyl 4-(13-ethoxy-6-ethyl-4-oxo-5-(2-oxo-2- phenylethyl)-4,5-dihydrothienoi|3,2-c|Ipyridine-2-ylcarbonylamino)dipiperidine-1-carboxylate (125 mg, 15 95) in the form of a white powder. 3-

Ethoxy-6-ethyl-4-oxo-5-(2-oxo-2-phenylethyl)-M-piperidin-4-yl-4,5-dihydrothienoi|3,2-s|pyridine-2-carboxamide (94 mg , 85 95) was obtained in the form of a white powder from tert-butyl 4-(P3-ethoxy-6-ethyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno|3 ,2-c|pyridin-2-yl|carbonyl)iamino)piperidine-1-carboxylate (125 mg, 0.22 mmol) using a method similar to the method given in Example 126. 2-I4-(((3 -Ethoxy-6-ethyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno|3,2-s|Ipyridine-2-ylcarbonylamino)piperidin-1-yl|-2- Oxoethyl acetate (80 mg, 18 96) was obtained as a white solid from the thus obtained 3-ethoxy-6b-ethyl-4-oxo-5-(2-oxo-2-phenylethyl)-M-piperidin-4-yl -4,5-Dihydrothieno3,2-c|Ipyridine-2-carboxamide (90 mg, 0.18 mmol) using a method similar to that given in Example 127.

A mixture of 2-I4-(|(3-ethoxy-6-ethyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoiI3,2-c|Ipyridine-2-ylcarbonylamino)piperidine -1-yl|-2-oxoethyl acetate (90 mg, 0.18 mmol) and potassium carbonate (39 mg, 0.28 mmol) in THF (8 mL)-methanol (2 mL)-water (2 mL) were stirred at at room temperature for 1 hour. The reaction mixture was concentrated, and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (64 mg, 69 95) as white crystals. "H-NMR (300 MHz, DMSO-α) 5: 1.17 (ZH, t, 9-74 Hu), 1.30 (ZH, t, 9- 7.1 Hu), 1.35-1.60 (2H, m), 1.90 (2H, d, U-9.9 Hu), 2.60 (2H, k, 9-74 Hz), 2 .84 (1H, t, U-12.0 Hz), 3.10 (1TN, t, 9U-14.0 Gu), 3.66 (1H, d, 9U-13.5

Hz), 4.00-4.09 (ZH, m), 4.28 (ZH, k, 9U-7.1 Hz), 4.50 (1H, t, 9U-5.4 Hz), 5, 66 (2H, s), 6.84 (1H, s), 7.60-7.68 (2H, m), 7.75 (1H, t, U-7.5 Hz), 8.10-8 ,13 (2H, m).

Example 651

Preparation of /1,6-dimethyl-N-(1-oxidotetrahydro-2H-thiopyran-4-yl)-4-oxo-5-(2-oxo-2-phenylethyl)-3-(2,2,2-trifluoroethoxy )-4,5-dihydro-1H-pyrrolo|3,2-s|Ipyridine-2-carboxamide o

With

M

Me, N

MORE with (6) in

Me I MF) and ex

Using a method similar to the method given in Example 571, 1,6-dimethyl-4-oxo-5-(2-oxo-2-phenylethyl)-M-(tetrahydro-2H-thiopyran-4-yl)-3- (2,2,2-trifluoroethoxy)-4,5-dihydro-1H-pyrrolo|3,2-s|Ipyridine-2-carboxamide (150 mg) as a white solid from the compound

Auxiliary Example 50 (200 mg, 0.47 mmol). The title compound (131 mg, 51 95) was obtained as white crystals from similarly prepared 1,6-dimethyl-4-oxo-5-(2-oxo-2-phenylethyl)-M-(tetrahydro-2H-thiopyran -4-yl)-3-(2,2,2-trifluoroethoxy)-4,5-dihydro-1H-pyrrolo|3,2-c|Ipyridine-2-carboxamide (150 mg) using a method similar to of the method given in Example 571. "H-NMR (300 MHz, DMSO-α) 5: 1.60-1.75 (1H, m), 1.83 (1H, d, 9U-10.2 Hz), 2.06-2.29 (5Н, m), 2.70-2.85 (2Н, m), 2.93 (1Н, d, U-12.9 Hz), 3.81 (ЗН, d, U-6.3 Hz), 3.90-4.10 (1TN, m), 5.00-5.13 (2N, m), 5.65 (2N, s), 6.64 (1N, s ), 7.61 (ZN, t, U-7.8 Hu), 7.74 (1H, t, U-7.2 Hu), 8.10-8.12 (2H, m).

Example 652

Preparation of 3-(2,2-difluoroethoxy)-6b-ethyl-M-(1-(hydroxyacetyl)piperidin-4-yl|-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)- 4,5-dihydro-1H-pyrrolo|3,2-s|Ipyridine-2-carboxamide

And h

M on sh,

M

Me, in H x s (6) -

ЕЙ M (in) E

By a method similar to that given in Example 140, the title compound (340 mg, 84 95) was obtained as a white amorphous solid from the compound of Auxiliary

Example 171 (300 mg, 0.72 mmol). "H-NMR (300 MHz, DMSO-av) 6: 1.19 (ZH, t, U-7.4 Hu), 1.20-1.50 (2H, m), 1.90 (2H, d , 9U-9.9 Hu), 2.59 (2H, k, 9U-7.4 Hu), 2.83 (IN, t, 9U-12.2 Hu), 3.09 (1H, t, U -11.7 Gu), 3.68 (1H, d, 9U-12.9 Hz), 3.90 (ZH, s), 3.95-4.20 (ZH, m), 4.26 (1H , d, 9-11.7 Hz), 4.51 (1H, t, 9U-5.4 Gu), 4.67 (2H, td, U-16.1, 3.0 Hz), 5.23 (1H, s), 5.61 (2H, s), 6.33 (1H, tt, U-54.2, 3.0 Gu), 7.49 (1H, d, U-7.8 Hz) , 7.61 (2H, t, U-7.5 Hz), 7.73 (1H, t, 9U-7.5

Hz), 8.10-8.12 (2H, m).

Example 653

Preparation of b-ethyl-M-P1-(hydroxyacetyl)piperidin-4-yl|-5-(3-methoxybenzyl)-1-methyl-4-oxo-3-

(2,2,2-trifluoroethoxy)-4,5-dihydro-1H-pyrrolo|3,2-s|Ipyridine-2-carboxamide

IF) ON

M what

Me, M

H oon, h

E M 6) su"

A mixture of the compound of Auxiliary Example 143 (200 mg, 0.456 mmol), 2-(4-aminopiperidin-1-yl)-2-oxoethanol hydrochloride (115 mg, 0.593 mmol), NEW (92.4 mg, 0.684 mmol), UUZSO ( 131 mg, 0.684 mmol), triethylamine (0.126 mL, 0.912 mmol) and DMF (4.0 mL) were stirred at room temperature for 16 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The extracts were combined, washed with water and saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography on amino silica gel (eluate; ethyl acetate). By recrystallization of the obtained solid from ethyl acetate, the title compound (162 mg, 61 95) was obtained as a white powder. "H-NMR (300 MHz, DMSO-av) 6: 1.16 (ZH, t, 9U-7.3 Hz), 1.24-1.50 (2H, m), 1.81-1.95 (2H, m), 2.60 (2H, k, uU7,Z Hz), 2.76-2.91 (1H, m), 3.01-3.18 (1H, m), 3.64- 3.74 (4Н, m), 3.84 (ЗН, с), 3.95-4.14 (ЗН, m), 4.20-4.33 (IN, m), 4.52 (1Н, t, 9U-5.4 Gu), 5.11 (2H, k, 9U-9.3 Hz), 5.32 (2H, w s), 6.49-6.64 (ZH, m), 6 ...

Example 654

Preparation of 5-benzyl-6-ethyl-M-(1-(hydroxyacetyl)piperidin-4-yl|-1-methyl-4-oxo-3-(2,2,2-trifluoroethoxy)-4,5-dihydro- 1 H-pyrrolo|Z,2-c|Ipyridine-2-carboxamide o on

M what

M

Me,

M

H oon, xx

Эи и о

Vp

By a procedure similar to that of Example 653, the title compound (182 mg, 75 90) was obtained as a white powder from the compound of Sub-Example 145 (180 mg, 0.441 mmol). "H-NMR (300 MHz, DMSO-av) 6: 1.16 (ZH, t, 9U-7.2 Hu), 1.25-1.48 (2 H, m), 1.83-1, 95 (2H, m), 2.60 (2H,

Kk, 97.2 Hz), 2.77-2.90 (1H, m), 3.02-3.17 (1H, m), 3.63-3.75 (1H, m), 3.84 (ZN, s), 3.96-4.14 (ZN, m), 4.20-4.33 (1Н, m), 4.52 (1Н, t, 95.5 Gu), 5.10 ( 2H, k, 9U-9.4 Hz), 5.36 (2H, w s), 6.52 (1H, s), 7.00-7.09 (2H, m), 7.19-7, 36 (ZH, m), 7.53 (1H, d, 9-2:7.7 Hz).

Example 655

Preparation of 5-(2,5-dimethoxybenzyl)-6-ethyl-M-(1-(hydroxyacetyl)piperidin-4-yl|-1-methyl-4-oxo-3-(2,2,2-trifluoroethoxy)- 4,5-dihydro-1H-pyrrolo|3,2-s|Ipyridine-2-carboxamide

(about) ON

M what

M

Me,

M

Their oo" eh

E M (c) ro

Ome

By a procedure similar to that of Example 653, the title compound (86.0 mg, 80 95) was obtained as a white powder from the compound of Auxiliary Example 147 (82.7 mg, 0.177 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.17 (ZH, t, 9U-7.3 Gu), 1.24-1.48 (2H, m), 1.84-1.93 (2Н, m), 2.52-2.61 (2Н, m), 2.77-2.90 (1Н, m), 3.03-3.16 (1Н, m), 3.55 (ЗН , c), 3.64-3.74 (1Н, m), 3.83 (ЗН, с), 3.86 (ЗН, с), 3.97-4.14 (ЗН, m), 4, 20-4.32 (1H, m), 4.52 (1H, t, 9U-5.3 Hz), 5.08 (2H, k, 9-9.2 Hz), 5.21 (2H, w s), 5.89 (1H, d, 93.0 Hz), 6.56 (1H, s), 6.79 (1H, dd, U-8.9, 3.0 Hz), 6.97 ( 1H, d, uU-8.9 Hz), 7.53 (1H, d, 927.9 Gu).

Example 656

Preparation of b-ethyl-M-(1-(hydroxyacetyl)piperidin-4-yl|-5-(2-(3-methoxyphenyl)-2-oxoethyl|-1-methyl-4-oxo-3-(2,2 ,2-trifluoroethoxy)-4,5-dihydro-1H-pyrrolo|3,2-s|Ipyridine-2-carboxamide (c) OH

M

WHAT,

M

Me,

M

H ot" eh

E M (6)

I

Ome

By a procedure similar to that of Example 653, the title compound (65.1 mg, 29 95) was obtained as a white powder from the compound of Auxiliary Example 151 (170 mg, 0.364 mmol). "H-NMR (300 MHz, DMSO-av) 6: 1.19 (ZH, t, 9U-7.3 Gu), 1.25-1.48 (2H, m), 1.82-1.95 (2H, m), 2.54-2.64 (2H, m), 2.76-2.90 (1H, m), 3.01-3.15 (1H, m), 3.62-3 .74 (1Н, m), 3.82-3.90 (6Н, m), 3.95-4.13 (ЗН, m), 4.20- 4.35 (1Н, m), 4.52 (1H, t, U-5.5 Hz), 5.05 (2H, k, 9U-9.3 Gy), 5.62 (2H, s), 6.54 (1H, s), 7.26 -7.35 (1Н, m), 7.46-7.62 (ЗН, m), 7.69-7.76 (1Н, m).

Example 657

Preparation of 5-(2-(3-chlorophenyl)-2-oxoethyl|-6-ethyl-M-(1-(hydroxyacetyl)piperidin-4-yl|-1-methyl-4-oxo-3-(2,2 ,2-trifluoroethoxy)-4,5-dihydro-1H-pyrrole|3,2-s|Ipyridine-2-carboxamide

IF) ON

M what

M kh

My tsv,

WITH

E M |) x p

By a procedure similar to that of Example 653, the title compound (160 mg, 64 95) was obtained as a white powder from the compound of Subsidiary Example 155 (192 mg, 0.408 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.19 (ZH, t, U-7.3 Gu), 1.25-1.49 (2H, m), 1.82-1.95 (2H, m), 2.60 (2H, k, uU7,Z Hz), 2.76-2.90 (1H, m), 3.01-3.17 (1H, m), 3.62- 3.74 (1Н, m), 3.86 (ЗН, с), 3.96-4.15 (ЗН, m), 4.20-4.32 (IN, m), 4.52 (1Н, t, 9U-5.4 Hu), 5.05 (2H, k, 929.2 Hu), 5.62 (2H, s), 6.55 (1H, s), 7.50 (1H, d, 9U-7.6 Gu), 7.61-7.69 (1H, m), 7.77-7.84 (1H, m), 8.03-8.09 (1H, m), 8.14 (IN, t, U-1.8 Hz).

Example 658

Preparation of b-ethyl-M-P1-(hydroxyacetyl)piperidin-4-yl|-5-(2-methoxybenzyl)-1-methyl-4-oxo-3-(2,2,2-trifluoroethoxy)-4,5 -dihydro-1H-pyrrolo|3,2-s|Ipyridine-2-carboxamide (e; he

M

IN,

Me MN

Mshko v

E m o

Meow

By a procedure similar to that of Example 653, the title compound (120 mg, 86 95) was obtained as a white powder from the compound of Auxiliary Example 157 (104 mg, 0.237 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.16 (ZH, t, U-7.4 Hu), 1.26-1.49 (2H, m), 1.81-1.95 (2H, m), 2.52-2.61 (2H, m), 2.77-2.91 (1H, m), 3.00-3.19 (1H, m), 3.56-3 .77 (1Н, m), 3.86 (ЗН, с), 3.88 (ЗН, с), 3.97-4.14 (ЗН, m), 4.19-4.33 (1Н, m ), 4.52 (1H, t, U-5.4 Hz), 5.08 (2H, k, U-9.2 Gu), 5.23 (2H, w s), 6.32-6, 40 (1H, m), 6.56 (1H, s), 6.76-6.85 (1H, m), 7.01-7.09 (1H, m), 7.17-7.28 ( 1H, m), 7.52 (1H, d, 9U-7.6 Hz).

Example 659

Preparation of b-ethyl-M-P1-(hydroxyacetyl)piperidin-4-yl|-5-(4-methoxybenzyl)-1-methyl-4-oxo-3-(2,2,2-trifluoroethoxy)-4,5 -dihydro-1H-pyrrolo|3,2-s|Ipyridine-2-carboxamide

(e) he

M sh,

M Shko

WITH

E m o

Ome

By a procedure similar to that of Example 653, the title compound (147 mg, 71 95) was obtained as a white powder from the compound of Auxiliary Example 159 (157 mg, 0.358 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.16 (ZH, t, U-7.3 Hu), 1.24-1.48 (2H, m), 1.83-1.96 (2H, m), 2.62 (2H, k, uU7,Z Hz), 2.76-2.91 (1H, m), 3.02-3.17 (1H, m), 3.63- 3.76 (4Н, m), 3.83 (ЗН, с), 3.95-4.14 (ЗН, m), 4.20-4.33 (IN, m), 4.52 (1Н, t, 9U-5.4 Hu), 5.11 (2H, k, 9U-9.4 Hu), 5.28 (2H, w s), 6.50 (1H, s), 6.83-6 .90 (2H, m), 6.96-7.05 (2H, m), 7.52 (1H, d, 9-7.7 Hz).

Example 660

Preparation of 5-(2-chlorobenzyl)-6-ethyl-M-(P1-(hydroxyacetyl)piperidin-4-yl|-1-methyl-4-oxo-3-(2,2,2-trifluoroethoxy)-4, 5-dihydro-1H-pyrrolo|3,2-s|Ipyridine-2-carboxamide) on

M o V,

Me MN

M

X o/z xx

E M (e,; a -

By a procedure similar to that of Example 653, the title compound (119 mg, 66 95) was obtained as a white powder from the compound of Auxiliary Example 161 (138 mg, 0.912 mmol). "H-NMR (300 MHz, DMSO-av) 6: 1.18 (ZH, t, 9U-7.3 Hz), 1.26-1.47 (2H, m), 1.82-1.94 (2H, m), 2.53-2.61 (2H, m), 2.76-2.90 (1H, m), 3.02-3.17 (1H, m), 3.61-3 .76 (1H, m), 3.86 (ZN, s), 3.95-4.14 (ZN, m), 4.19-4.33 (IN, m), 4.46-4.56 (1H, m), 5.06 (2H, k, 9U-9.4 Hz), 5.33 (2H, s), 6.45-6.55 (1H, m), 6.60 (1H, c), 7.21-7.32 (2H, m), 7.45-7.60 (2H, m).

Example 661

Preparation // b-ethyl-M-I|1-(hydroxyacetyl)piperidin-4-yl|-1-methyl-4-oxo-5-(2-phenylethyl)-3-(2,2,2-trifluoroethoxy) -4,5-dihydro-1H-pyrrolo|3,2-s|Ipyridine-2-carboxamide o; he

M o V,

Me MN

M

In 0 and sez xx c)

ESF);

RI

By a procedure similar to that of Example 653, the title compound (123 mg, 65 95) was obtained as a white powder from the compound of Auxiliary Example 165 (143 mg, 0.339 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.21 (ZH, t, U-7.2 Gu), 1.25-1.49 (2H, m), 1.82-1.94 (2H, m), 2.66 (2H, k,

U7.2 Hz), 2.77-2.95 (ЗН, m), 3.02-3.17 (1Н, m), 3.62-3.75 (1Н, m), 3.82 (ЗН , c), 3.95-4.35 (6H, m), 4.52 (1H, t, U5.5 Hz), 5.12 (2H, k, 9U-9.4 Gu), 6.44 (1H, s), 7.16-7.35 (5H, m), 7.49 (1H, d, U-7.6 Hz).

Example 662

Preparation of 5-(3-chlorobenzyl)-6-ethyl-M-(P1-(hydroxyacetyl)piperidin-4-yl|-1-methyl-4-oxo-3-(2,2,2-trifluoroethoxy)-4, 5-dihydro-1H-pyrrolo|3,2-s|Ipyridine-2-carboxamide o)one

M cheeks,

Me MN

M

Their education

EE m o

By a procedure similar to that of Example 653, the title compound (261 mg, 71 95) was obtained as a white powder from the compound of Auxiliary Example 167 (281 mg, 0.635 mmol). "H-NMR (300 MHz, DMSO-av) 6: 1.17 (ZH, t, 9U-7.2 Hz), 1.23-1.50 (2H, m), 1.81-1.95 (2Н, m), 2.60 (2Н, k, 9-7.2 Hz), 2.76-2.92 (1Н, m), 3.02-3.17 (1Н, m), 3, 64-3.76 (1H, m), 3.85 (ZN, s), 3.95-4.15 (ZN, m), 4.19-4.36 (IN, m), 4.52 ( IN, t, 9U-5.4 Hz), 5.09 (2H, k, 9U-9.4 Gu), 5.35 (2H, w s), 6.55 (1H, s), 6.95 -7.03 (1H, m), 7.07-7.15 (IN, m), 7.25-7.40 (2H, m), 7.55 (1H, d, 9-76 Hz).

Example 663

Preparation of 5-(4-chlorobenzyl)-6-ethyl-M-(P1-(hydroxyacetyl)piperidin-4-yl|-1-methyl-4-oxo-3-(2,2,2-trifluoroethoxy)-4, 5-dihydro-1H-pyrrolo|3,2-s|Ipyridine-2-carboxamide

(c) he

M cheeks,

Me MN

M

In is v

EE M (c) . SI

By a procedure similar to that of Example 653, the title compound (160 mg, 65 95) was obtained as a white powder from the compound of Sub-Example 169 (188 mg, 0.425 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.16 (ZH, t, U-7.2 Hu), 1.23-1.49 (2H, m), 1.82-1.95 (2H, m), 2.59 (2H, k, uU7.2 Hz), 2.77-2.90 (1H, m), 3.00-3.17 (1H, m), 3.62- 3.76 (1Н, m), 3.84 (ЗН, с), 3.95-4.14 (ЗН, m), 4.21-4.34 (1Н, m), 4.52 (1Н, t, 9U-5.5 Hz), 5.09 (2H, k, 9U-9.4 Gu), 5.33 (2H, w s), 6.53 (1H, s), 7.03-7 ,12 (2H, m), 7.34-7.42 (2H, m), 7.53 (1H, d, 9U-7.6 Hz).

Example 664

Preparation of Benzyl /4-(3-methoxy-5-(4-methoxybenzyl)-4-oxo-4,5-dihydrothienoyl-3,2-c|quinolin-2-yl|carbonylamino)piperidine-1-carboxylate (e;

U-o 5-0 m,

M

R z tOME

Mmmmmmm -

By a method similar to that given in Example 25, the title compound (3.07 g, 79 95) was obtained as a white powder from the compound of Auxiliary Example 13 (2.5 g, 6.31 mmol) and benzyl 4-aminopiperidine -1-carboxylate hydrochloride (2.56 g, 9.46 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.15-1.64 (2H, m), 1.87 (2H, w d, U-9.6 Hz), 2.90-3, 10 (2H, w), 3.69 (ЗН, s), 4.00 (2H, d, 9-11.4 Hz), 4.09 (4H, s), 5.10 (2H, s), 5.53 (2H, w s), 6.87 (2H, d, 9-8.7 Hz), 7.20 (2H, d, 9U-8.7 Hz), 7.28-7.40 ( 6H, m), 7.49-7.56 (2H, m), 7.80 (1H, d, 9U-8.1 Hz), 8.00 (1H, d, 9U-8.4 Hz).

Example 665

Preparation of 3-methoxy-5-(4-methoxybenzyl)-4-oxo-M-piperidin-4-yl-4,5-dihydrothieno|3,2-c|quinoline-2-carboxamide

N

Mm,

M

5- N hi tOME

I F)

MeO -

A mixture of the compound of Example 664 (300 mg, 0.49 mmol), 10 Pho Ra-C (60 mg) and THF (20 ml)-methanol (10 ml) was stirred at room temperature for 24 hours under a hydrogen atmosphere. The catalyst was filtered off, the filtrate was concentrated and recrystallized from methanol-diethyl ether to give the title compound (154 mg, 66 95) as pale yellow crystals. "H-NMR (300 MHz, DMSO-α) 5: 1.48 (2H, k, 9-11.0 Hu), 1.82 (2H, d, U-9.6 Hz), 1.95- 2.15 (1H, w), 2.56 (2H, t, U-8.4 Gu), 2.93 (2H, d, 9U-12.6 Hz), 3.33 (ZH, s), 3.70 (ZH, s), 3.80-4.00 (1H, w), 4.10 (ZH, s), 5.53 (2H, w s), 6.86 (2H, d, 9U -8.7 Hz), 7.20 (2H, d, U-8.4 Hz), 7.30 (1H, t, 9U-7.1 Hz), 7.49-7.58 (2H, m ), 7.72 (IN, d, y-8.1 Hz), 8.00 (1H, d, 9-7.8 Hz).

Example 666

Preparation of M-P1-(2-hydroxyethyl)piperidin-4-yl|-3-methoxy-5-(4-methoxybenzyl)-4-oxo-4,5-dihydrothienoyl3,2-syquinoline-2-carboxamide (Fin!

Mm,

M

5- N hi tOME

M'o o

By a procedure similar to that of Example 79, the title compound (110 mg, 68 95) was obtained as a white solid from the compound of Example 665 (150 mg, 0.31 mmol). "H-NMR (300 MHz, SOSIv) 6: 1.55-1.74 (2H, m), 2.00-2.11 (2H, m), 2.36 (2H, t, 9U-11, 6 Gu), 2.58 (2H, t, 925.4 Hz), 2.84 (ZH, w s), 3.65 (2H, t, 9-5.4 Hz), 3.75 (ZH, s), 4.05-4.20 (1H, shu, 4.20 (ZH, s), 5.53 (2H, sh s), 6.83 (2H, dd, 9U-6.9, 1, 8 Hz), 7.17-7.26 (ZH, m), 7.35 (1H, d, 9U-8.1 Hz), 7.41-7.46 (1H, m), 7.64 ( 1H, d, 97.8 Hz), 7.85 (1H, dd, 9-7.8, 1.5 Hz).

Example 667

Preparation of /- M-(1-(2-hydroxyethyl)piperidin-4-yl|-3-methoxy-4-oxo-4,5-dihydrothienoic|Z,2-c|quinoline-2-carboxamide red

M

M

5-4. live tome

M'

N

A solution of the compound of Example 666 (110 mg, 0.21 mmol), anisole (91 mg, 0.84 mmol) and trifluoromethanesulfonic acid (0.5 mL) in trifluoroacetic acid (2 mL) was stirred at 80 C for 1 hour. After cooling, the reaction mixture was concentrated and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic phase was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluate; ethyl acetate/hexane-1/1-2/1) to give the title compound (60 mg, 71 95) as a white solid. "H-NMR (300 MHz, COSiz) 6: 1.60-1.76 (2H, m), 2.07 (2H, d, 9U-14.4 Gu), 2.36 (2H, t, U -10.1 Gu), 2.59 (2H, t, 9U-5.4 Hz), 2.88 (2H, d, 9U-11.4 Hz), 3.65 (2H, t, U-5 ,4 Hu), 3.70-3.80 (2H, shu, 4.00-4.15 (1H, m), 4.22 (ZH, s), 6.76-6.85 (1H, m ), 7.32 (1H, t, 9-81 Hu), 7.51 (1H, t, U-8.4 Hu), 7.85 (1H, d, 9-81 Hu), 10.20- 10.50 (IN, w).

Example 668

Preparation of tert-butyl 4-(C3-methoxy-5-(4-methoxybenzyl)-1-methyl-4-oxo-4,5-dihydro-1H-pyrrolo|3,2-c)quinoline-2-ylcarbonyl) amino)piperidine-1-carboxylate o

In o

MO Zh-Me

Me Me (6)

M

Me Ts

X hmm tOME

Mo

meo -

By a procedure similar to that of Example 25, the title compound (3.45 g, 95 95) was obtained as a beige solid from the compound of Auxiliary Example 107 (2.49 g, 6.35 mmol) and tert- butyl 4-aminopiperidine-1-carboxylate (2.54 g, 12.69 mmol). "H-NMR (300 MHz, DMSO-av) 6: 1.35-1.49 (11H, m), 1.85 (2H, dd, 9U-12.6, 2.7 Hz), 2.89 -2.96 (2H, m), 3.69 (ZH, s), 3.88 (2H, d, 9-13.5 Hz), 3.96-4.09 (4H, m), 4, 27 (ZH, s), 5.40-5.60 (2H, w), 6.83-6.88 (2H, m), 7.14 (2H, d, 9U-8.7 Hz), 7 ,24-7.30 (1H, m), 7.41-7.49 (2H, m), 7.97 (1H, d, 9-81 Gu), 8.33 (1H, d, 9-81 Hz).

Example 669

Preparation of 3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-M-(pyrrolidin-33-ylmethyl)-4,5-dihydrothienoic acid, 3,2-siquinoline-2-carboxamide hydrochloride

Rhy TOME NOI m so:

According to a method similar to the method given in Example 25, tert-butyl 3-(((3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoi|3,2-s |quinoline-2-ylcarbonylamino)methyl|pyrrolidine-1-carboxylate (530 mg, 72 95) was obtained as a white powder from the compound of Auxiliary Example 7 (500 mg, 1.27 mmol) and 3-(aminomethyl)-1-Boc -pyrrolidine (381 mg, 1.90 mmol).

By a procedure similar to that of Example 500, the title compound (456 mg, 97 95) was obtained as a white powder from tert-butyl. 3-((3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothienoi|3,2-c|quinoline-2-ylcarbonylamino)methyl|pyrrolidine-1-carboxylate ( 530 mg, 0.92 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.55-1.73 (1H, m), 1.90-2.10 (1H, m), 2 ... 2H, s), 7.35 (1H, t, 9U-7.5 Hz), 7.49-7.67 (5H, m), 7.77 (1H, t, 9U-7.4

Hz), 8.05 (TN, d, 9U-7.8, Hz), 8.16-8.19 (2Н, m), 8.25 (1Н, т, У-5.9 Gu), 9 ,04 (2H, w s).

Example 670

Preparation of tert-butyl 3-(13-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo|3,2-c)quinoline- 2-ylcarbonyl)amino)azetidine-1-carboxylate (6)

In o

MO Zh-Me o u Me Me

M

Me, in N

X and OMe

I Shk o) r:

By a procedure similar to that of Example 25, the title compound (610 mg, 88 90) was obtained as a white powder from the compound of Auxiliary Example 28 (500 mg, 1.27 mmol) and 3-amino-1-Boc- azetidine (330 mg, 1.92 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.40 (9Н, m), 3.85-3.95 (2Н, m), 3.99 (ЗН, с), 4.14 (2Н , t, U-7.8 Gu), 4.27 (ZH, s), 4.62-4.74 (1H, m), 5.97 (2H, s), 7.31 (1H, t, 9U-7.5 Hz), 7.38 (1H, d, 9U-8.1 Hz), 7.48 (1H, t, U-7.5

Hz), 7.64 (2H, t, 9U-7.5 Hz), 7.76 (1H, t, U-7.5 Hz), 8.16-8.19 (2H, m), 8, 37 (1H, d, U-8.1 Gu), 8.56 (1H, d,

U-7.2 Hz).

Example 671

Preparation of tert-butyl 3-((3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo|3,2-c)quinoline -2-ylcarbonyl)amino)cyclohexylcarbamate

N vd; o) o

M X Nn Me Me zt OMe mmO re

By a procedure similar to that of Example 25, the title compound (395 mg, 66 95) was obtained as a white powder from the compound of Auxiliary Example 7 (400 mg, 1.02 mmol) and tert-butyl (33-aminocyclohexyl) carbamate (285 mg, 1.33 mmol). "H-NMR (300 MHz, DMSO-α) 5: 0.98-1.46 (13 H, m), 1.65-1.90 (Z H, m), 2.00-2.12 ( 1 N, m), 3.23-3.42 (1

Н, m), 3.73-3.88 (1 Н, m), 3.р96 (2Н, s), 4.04 (1Н, s), 4.30 (2 Н, s), 4.35 (1 N, s), 5.97 (2 N, s), 6.76-6.94 (1

N, m), 7.24-7.42 (2 N, m), 7.43-7.53 (1 N, m), 7.63 (2 N, t, U-7.6 Hz), 7.71-7.80 (1 N, m), 7.86 (1 N, d, 9U-7.9

Hz), 8.12-8.22 (2 N, m), 8.31-8.42 (1 N, m).

Example 672

Preparation of 2-(4-C(3-methoxy-1-methyl-4-oxo-4,5-dihydro-1H-pyrrolo|3,2-c|quinolin-2-yl)ucarbonylamino)piperidin-1-yl )-2-oxoethyl acetate o o o o-th

In Me

M shk,

Me, MN sh with OMe

M Ge;

N

The compound of Example 558 (500 mg, 0.7 mmol), anisole (376 mg, 3.48 mmol) and trifluoromethanesulfonic acid (2 ml) were dissolved in trifluoroacetic acid (9 ml) and the mixture was stirred at 80 C for 2 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was diluted with a saturated aqueous solution of sodium bicarbonate and extracted using THF-ethyl acetate. The extract was concentrated to give 3-methoxy-1-methyl-4-oxo-N-piperidin-4-yl-4,5-dihydro-1H-pyrrolo|3,2-c|quinoline-2-carboxamide (1.10 d) in the form of a beige solid substance.

To a solution of 3-methoxy-1-methyl-4-oxo-M-piperidin-4-yl-4,5-dihydro-1H-pyrrolo|3,2-c|quinoline-2-carboxamide (300 mg, 0, 87 mmol) and triethylamine (88 mg, 0.87 mmol) in THF (30 mL) was added acetoxyacetyl chloride (119 mg, 0.87 mmol) while cooling on ice, and the mixture was stirred for 2 h. The reaction mixture was diluted with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated. The resulting solid was washed with diethyl ether-hexane to give the title compound (221 mg, 56 95) as a white solid. "H-NMR (300 MHz, DMSO-α) 6: 1.30-1.65 (2H, m), 1.80-2.00 (2H, m), 2.09 (ZH, s), 2 .90 (2H, t, 9-11.4

Hz), 3.19 (2H, t, 9U-11.4 Hz), 3.70 (2H, d, 9U-13.5 Hz), 4.02-4.19 (AN, m), 4, 28 (ZN, s), 7.22 (1H, t, 9U-7.5 Gu), 7.40-7.48 (2H, m), 7.93 (IN, d, 97.5 Gu), 8.24 (1H, d, 9U-8.4 Gu), 11.34 (1H, s).

Example 673

Preparation of tert-butyl 4-((8-fluoro-33-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno|3,2- sequinolin-2-ylcarbonyl)iamino) piperidine-1-carboxylate

Me Me

AND); Hmmm

In o

Msh, village

N

H

E shh OMe

And what) I

By a procedure similar to that of Example 25, the title compound (486 mg, 84 95) was obtained as a white solid from the compound of Sub-Example 116 (400 mg, 0.97 mmol) and tert-butyl 4-aminopiperidine -1-carboxylate (234 mg, 1.2 mmol). "H-NMR (300 MHz, SOS") 6: 1.40-1.53 (11Н, m), 1.96-2.11 (2Н, m), 2.92-3.10 (2Н, m ), 3.95-4.08 (2H, m), 4.10-4.24 (4H, m), 5.85 (2H, s), 6.99 (1H, dd, 9U-9.3 , 4.3 Hz), 7.15-7.25 (1H, m), 7.50-7.62 (4H, m), 7.65-7.74 (IN, m), 8.05- 8.16 (2H, m).

Example 674

Preparation of tert-butyl 4-((8-fluoro-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrroloyi3,2-c) quinoline-2-ylcarbonylamino)piperidine-1-carboxylate

Me Me Oh Me

Uh-oh

M

KO,

M

H

Ehhh OMe

And MF) i

By a procedure similar to that given in Example 25, the title compound (2.5 g, 87 95) was obtained as a white solid from the compound of Auxiliary Example 119 (2.0 g, 4.9 mmol) and tert- butyl 4-aminopiperidine-1-carboxylate (1.2 g, 5.9 mmol). "H-NMR (300 MHz, SOSI") 5: 1.34-1.53 (11Н, m), 1.89-2.13 (2Н, m), 2.94-3.14 (2Н, m ), 3.89-4.07 (2H, m), 4.08-4.24 (AN, m), 4.46 (ZH, s), 5.87 (2H, s), 6.93- 7.04 (1H, m), 7.08-7.21 (1H, m), 7.48-7.60 (2H, m), 7.62-7.75 (2H, m), 7, 94 (1H, dd, 9U-10.0, 2.8 Gu), 8.04-8.20 (2H, m).

Example 675

Preparation of 8-fluoro-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-M-piperidin-4-yl-4,5-dihydro-1H-pyrroloyl3,2-siylquinoline -2-carboxamide hydrochloride

But her

M

Me, M

M. H

E xx OMe and. MF) x

By a procedure similar to that of Example 542, the title compound (1.6 g, 72 U) was obtained as a pale yellow solid from the compound of Example 674 (2.5 g, 4.3 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.62-1.86 (2H, m), 1.96-2.13 (2H, m), 2.95-3.14 (2H, m), 3.21-3.47 (2Н, m), 3.95 (ЗН, с), 4.02-4.18 (1Н, m), 4.27 (ЗН, с), 5.98 (2H, s), 7.23-7.51 (2H, m), 7.57-7.68 (2H, m), 7.71-7.84 (IN, m), 8.04-8 .26 (AN, m), 8.64 (2H, w s).

Example 676

Preparation of 2-I4-(18-fluoro-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo|3,2-s )quinoline-2-ylcarbonyl)amino)piperidine-1-yl|-2-oxoethyl acetate (c) about 0-4 units of Me

M

M

Me, y

M

H

Ehhh OMe

And Me) I

By a procedure similar to that of Example 544, the title compound (293 mg, 87 95) was obtained as a white solid from the compound of Example 675 (300 mg, 0.57 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.30-1.65 (2H, m), 1.82-1.96 (2H, m), 2.08 (ZH, s), 2 .80-2.96 (1H, m), 3.08-3.26 (1H, m), 3.65-3.78 (1H, m), 3.96 (ZH, s), 4.02 -4.22 (2H, m), 4.30 (ZH, s), 4.74-4.85 (2H, m), 5.97 (2H, s), 7.29-7.50 (2H , m), 7.57-7.68 (2Н, m), 7.72-7.81 (1Н, m), 7.98-8.06 (1Н, m), 8.07-8.21 (ZN, m).

Example 677

Preparation of M-(1-benzyl-3-methylpiperidin-4-yl)-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo |3,2-s|quinoline-2-carboxamide

M u k

M Meke N

Their xx OMe

I. Shk c) x

To a solution of 1-benzyl-3-methylpiperidin-4-one (227 mg, 1.1 mmol) and ammonium acetate (861 mg, 11 mmol) in methanol (9.0 mL) was added sodium triacetoxyborohydride (750 mg , 3.5 mol) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with 1M sodium hydroxide solution, and the aqueous layer was extracted twice with ethyl acetate. The extracts were combined, dried over magnesium sulfate and concentrated under reduced pressure. To a solution of the residue, the compounds of Auxiliary Example 28 (396 mg, 1.0 mmol) and NOVI (151 mg, 1.1 mol) in DMF (7.0 mL) was added M/5CO (215 mg, 1.1 mmol) at cooled on ice and the mixture was stirred at room temperature for 15 hours. The reaction mixture was diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate. The extracts were combined, washed with saturated saline, dried over magnesium sulfate and passed through amino silica gel. The filtrate was concentrated under reduced pressure. The residue was purified by chromatography on amino silica gel (eluate; ethyl acetate/hexane-30/70-100/0) and recrystallized from ethyl acetate-hexane to give the title compound (373 mg, 64 95) as a white solid. "H-NMR (300 MHz, DMSO-av) 6: 0.83-1.01 (ZH, m), 1.49-2.40 (5H, m), 2.56-2.89 (1H, m), 3.22-3.59 (ЗН, m), 3.94-4.04 (ЗН, m), 4.07-4.20 (1Н, m), 4.25-4.41 ( ЗН, m), 5.98 (2Н, с), 7.16-7.42 (7Н, m), 7.43-7.54 (1Н, m), 7.58-7.69 (2Н, m), 7.72-7.81 (1Н, m), 7.82-7.94 (1Н, m), 8.10-8.23 (2Н, m), 8.28-8.45 ( 1H, m).

Example 678

Preparation of 3-methoxy-1-methyl-N-(3-methylpiperidin-4-yl)-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolyl3,2-s |quinoline-2-carboxamide

N in o)

M M Me still N

X xx OMe

M (c); h

To a solution of the compound of Example 677 (373 mg, 0.65 mmol) in THF (40 mL) was added 1-chloroethyl chloroformate (0.67 mL, 6.5 mol) while cooling on ice, and the mixture was stirred at room temperature for 3 hours. While cooling on ice, 1-chloroethyl chloroformate (0.67 mL, 6.5 mol) and diisopropylethylamine (0.30 mL, 3.2 mmol) were added, and the mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure and the residue was washed with diethyl ether. The residue was dissolved in methanol (50 mL) and the mixture was stirred at room temperature for 7 hours and concentrated under reduced pressure. The residue was purified by chromatography on amino silica gel (eluate; methanol/ethyl acetate-0/100-10/90) and recrystallized from ethyl acetate-hexane to give the title compound (90 mg, 29 95) as a pale brown solid. "H-NMR (300 MHz, DMSO-α) 6: 0.83-0.95 (ЗН, m), 1.21-2.35 (5Н, m), 2.60-3.01 (ЗН, m), 3.94-4.08 (ЗН, m), 4.11-4.22 (1Н, m), 4.26-4.41 (ЗН, m), 5.98 (2Н, с) , 7.22-7.42 (2H, m), 7.43-7.53 (1H, m), 7.59-7.69 (2H, m), 7.71-8.00 (2H, m), 8.12-8.22 (2Н, m), 8.32-8.45 (1Н, m).

Example 679

Preparation of tert-butyl (1-C3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo|3,2-c)quinoline- 2-ylcarbonyl)piperidin-4-yl/ucarbamate (c) o) Ume

M

X with OMe

M (in) x

By a procedure similar to that of Example 25, the title compound (440 mg, 86 95) was obtained as a white solid from the compound of Sub-Example 28 (350 mg, 0.90 mmol) and tert-butyl piperidine-4 -ylcarbamate (198 mg, 0.99 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.25-1.51 (11Н, m), 1.68-1.94 (2Н, m), 2.91-3.07 (1Н, m), 3.10-3.27 (IN, m), 3.47-3.65 (1Н, m), 3.67-3.82 (1Н, m), 3.88 (ЗН, с) , 3.95-4.06 (ZH, m), 4.29-4.48 (1H, m), 5.97 (2H, s), 6.93 (IN, d, U-6.2 Gu ), 7.24-7.51 (ZH, m), 7.57-7.69 (2H, m), 7.70-7.83 (1H, m), 8.11-8.23 (2H , m), 8.32 (1H, dd, 3-8,3,11 Gu).

Example 680

Preparation of tert-butyl 4-(3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo|3,2-c|quinoline- 2-ylcarbonyl)piperazine-1-carboxylate

Me (about); /lt o-«-Me

Me Mo M-o0 Me "M x / o

X xx OMe

M (in) x

By a procedure similar to that of Example 25, the title compound (571 mg, quant.) was obtained as a white solid from the compound of Auxiliary Example 28 (400 mg, 1.0 mmol) and tert-butyl piperazine-1 -carboxylate (210 mg, 1.1 mmol). "H-NMR (300 MHz, SOSIz) 5: 1.49 (9H, s), 3.43-3.88 (8H, m), 4.05 (ZH, s), 4.08-4.12 (ZH, m), 5.89 (2H, s), 7.01-7.10 (1H, m), 7.20-7.31 (1H, m), 7.35-7.44 (1H , m), 7.50-7.59 (2Н, m), 7.62-7.71 (1Н, m), 8.07-8.14 (2Н, m), 8.20 (1Н, dd , U-8.2, 1.2 Hz).

Example 681

Preparation of 3-methoxy-5-(4-methoxybenzyl)-1-methyl-4-oxo-M-piperidin-4-yl-4,5-dihydro-1H-pyrrolo|3,2-c)quinoline-2- carboxamide hydrochloride

N

M mk,

Me. Monet m-. In the same volume

To a solution of the compound of Example 558 (500 mg, 0.87 mmol) in ethyl acetate (15 mL) was added a 4M solution of hydrochloride in ethyl acetate (5 mL) and the mixture was stirred at room temperature for 4 hours.

The resulting residue was collected by filtration, washed with diethyl ether and dried under reduced pressure to give the title compound (440 mg, 99 95) as a pale pink powder. "H-NMR (300 MHz, DMSO-α) 6: 1.78 (2H, k, U-10.3 Hu), 2.05 (2H, d, 9U-10.8 Hu), 3.06 ( 2H, t, 9U-10.7

Hz), 3.26-3.33 (2Н, m), 3.63 (ЗН, s), 4.02 (ЗН, s), 4.09-4.13 (1Н, m), 4.24 (ZH, s), 5.40-5.60 (2H, w), 6.86 (2H, d, U9-8.7 Hz), 7.14 (2H, d, 9U-8.7 Hz) , 7.25-7.30 (1H, m), 7.42-7.49 (2H, m), 8.15 (1H, d, U-7.5 Hz), 8.33 (IN, d , U-7.8 Gu), 8.60-8.90 (2H, pc).

Example 682

Preparation of M-(1-(2-hydroxyethyl)piperidin-4-yl|-3-methoxy-5-(4-methoxybenzyl)-1-methyl-4-oxo-4,5-dihydro-1H-pyrroloyi3,2- c|quinoline-2-carboxamide ud

M shO,

Me. M - In hmm tOME

I. M c)

meo -

By a procedure similar to that of Example 79, the title compound (1.91 g, 75 95) was obtained as white crystals from the compound of Example 681 (2.50 g, 4.89 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.58 (2H, k, 9U-9.9 Hz), 1.85 (2H, d, 9U-9.6 Hz), 2.18 ( 2H, t, 9U-9.9 Hz), 2.40 (2H, t, 9-63 Hz), 2.78 (2H, d, 9-11.4 Gu), 3.50 (2H, k, U-6.0 Hz), 3.69 (ZH, s), 3.70-3.85 (1H, w), 4.04 (ZH, s), 4.29 (ZH, s), 4, 35-4.40 (1H, m), 5.40-5.65 (2H, w), 6.86 (2H, d, 9U-8.7 Hz), 7.14 (2H, d, U- 8.4 Gu), 7.24-7.30 (1H, m), 7.42-7.49 (2H, m), 7.91 (IN, d, 9U-7.8 Hz), 8, 33 (1H, d, 9U-8.1 Hz).

Example 683

Preparation of М-P1-(2-hydroxyethyl)piperidin-4-yl|-3-methoxy-1-methyl-4-oxo-4,5-dihydro-1H-pyrrolo|3,2-quinoline-2-carboxamide

AI

M shO,

Me. M - hi tOME

M'

N

By a procedure similar to that of Example 672, the title compound (457 mg, 33 95) was obtained as white crystals from the compound of Example 682 (1.79 g, 3.45 mmol). "H-NMR (300 MHz, DMSO-α) 6: 1.50-1.60 (2H, m), 1.83 (2H, d, 9U-10.2 Hz), 2.18 (2H, t , U-10.4 Gu), 2.40 (2H, t, U-6.3 Hz), 2.65-2.85 (2H, m), 3.50 (2H, k, 9U-6, 0 Hz), 3.75-3.90 (1H, m), 4.03 (ZH, s), 4.29 (ZH, s), 4.38 (IN, t, 9U-5.4 Hz) , 7.22 (IN, t, 9U-7.5 Gu), 7.40-7.45 (2Н, m), 7.84 (1Н, d, У-7.8 Hz), 8.24 ( 1H, d, 9-81 Gu), 11.33 (1H, s).

Example 684

Preparation of β-ethyl-M-(|1-(hydroxyacetyl)piperidin-4-yl|-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-3-(2,2,3 ,3-tetrafluoropropoxy)-4,5-dihydro-1H-pyrrolo|3,2-s|Ipyridine-2-carboxamide vch

M

what

Me, M

M

H

I (in); What?

E M (c) and E Y

By a procedure similar to that of Example 140, the title compound (224 mg, 74 95) was obtained as a white powder from the compound of Sub-Example 175 (234 mg, 0.50 mmol). "H-NMR (300 MHz, DMSO-av) 6: 1.19 (ZH, t, 9U-7.4 Gu), 1.24-1.48 (2H, m), 1.82-1.95 (2Н, m), 2.58 (2Н, k, 97.4 Hz), 2.70-2.89 (1Н, m), 3.00-3.16 (1Н, m), 3.62- 3.78 (1H, m), 3.87 (ZH, s), 3.96-4.15 (ZH, m), 4.23-4.38 (IN, m), 4.53 (1H, t, U-5.4 Hz), 4.94 (2H, t, 9U-14.7 Hz), 5.63 (2H, s), 6.53 (1H, s), 6.66 (1H, tt, 9U-52.0, 5.2

Hz), 7.52 (IN, d, 9U-7.7 Hz), 7.57-7.66 (2H, m), 7.70-7.78 (1H, m), 8.08-8 ,16 (2H, m).

Example 685

Preparation of 3-(cyclopropylmethoxy)-6b-ethyl-IM-/1-(hydroxyacetyl)piperidin-4-yl|-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5- dihydro-1 H-pyrrolo|Z3,2-s|Ipyridine-2-carboxamide un

Mm,

Me. M schu (c) -1

E MO re

By a method similar to that of Example 140, the title compound (100 mg, 76 95) was obtained as a colorless powder from the compound of Auxiliary Example 177 (98 mg, 0.24 mmol). "H-NMR (300 MHz, DMSO-α) 6:0.19-0.27 (2Н, m), 0.46-0.55 (2Н, m), 1.06-1.20 (1Н, m), 1.18 (ZH, t, 9-74 Hz), 1.25-1.56 (2Н, m), 1.84-2.00 (2Н, m), 2.57 (2Н, k , 9-7.3 Hu), 2.77-2.94 (1Н, m), 3.04-3.20 (1Н, m),

C3.60-3.75 (1H, m), 3.91 (ZH, s), 3.96-4.13 (ZH, m), 4.17 (2H, d, 9-7.2 Gu) , 4.20-4.32 (1H, m), 4.51 (1H, t, 9-5.5 Hz), 5.59 (2H, s), 6.48 (1H, s), 7, 56-7.66 (2H, m), 7.69-7.81 (2H, m), 8.07-8.15 (2H, m).

Recipe Example 1

A pharmaceutical agent containing the compound of the present invention as an active ingredient can be prepared, for example, according to the following recipe. 1. capsule (1) compound obtained in Example 25 40 mg (2) lactose 70 mg (3) microcrystalline cellulose 9 mg (4) magnesium stearate 1 mg 1 capsule 120 mg (1), (2), (3) 1/2 of the component (4) is mixed, granulated, and the remainder (4) is added there, and gelatin capsules are filled with the resulting mixture. 2. tablet (1) compound obtained in Example 25 40 mg (2) lactose 58 mg (3) corn starch 18 mg (4) microcrystalline cellulose 3.5 mg (5) magnesium stearate 0.5 mg 1 tablet 120 mg (1) , (2), (3), 2/3 (4) and 1/2 (5) are mixed and granulated. The residue (4) and (5) are added to the granules. The mixture is pressed into tablets

Recipe example 2

The compound obtained in Example 25 (50 mg) is dissolved according to the Japanese Pharmacopoeia in distilled water for injection (50 ml) and made up to 100 ml with distilled water for injection according to the Japanese Pharmacopoeia. This solution is filtered under sterile conditions. Take a solution (1 ml) and fill it into a bottle for injection under sterile conditions, sublimate and seal.

Experimental examples

The genetic engineering methods described in the Experimental Examples below are based on the methods described in the book (Mapiaii5 et al., MoIesshiag Siopipd, Soia 5rgipd Nagbog I arogayogu, 1989) and the attached reagent protocol.

Experimental Example 1. Construction of the sii reporter plasmid The sii reporter plasmid was constructed by inserting 8 x Sii-binding site and the chicken 5-crystallin promoter in front of the Ishsia gene of swarm Z (Rgoteda). 5-Crystalline promoter was cloned using the PCR method using, as a set of primers, synthetic DNA 5-vbAAdaAtotasslasSsaaastoSasvoo-3 (BO IU MO: 1) 5-SSSAAlaSsTIoTasoSasASAaassstasto-3' (5EO I MO: 2)

obtained with reference to the main sequence described in SepVapkK samples under Mo.; XO2187, and chicken genome DNA (Siopiesp) as a template. The PCR reaction was performed using Rish Tigro (Zigaiadepe) and the following attached protocol. The resulting 108-br fragment was cleaved with restriction enzymes Vo and Nipap, and inserted into VaP-Nipa! roi3Z site with the production of the plasmid roi 3/5-sgu promoter.

As an 8 x Sii-binding site, a sequence was obtained from synthetic DNA containing eight 9-br Sii binding consensus sequences (ZASSASSSA), described in the work of Moop et al., 9. Vioi.

Spet., volume 273, p. 3496-3501 (1998). That is, two synthetic DNAs - savaatTASSadASSASSASSAaASSASSASSAVASASSASSASSAPASSASSASSAPASSASSASSACHASSASSASSASSASSA

СССАПАССАССААСАСТТТО-3 (5ЕО ЙУ МО: 3) - ваААСАСТТеаСсЯТеаатставстааATSтаастасастастотевататстастатстастаастотастаатТСОаатаАСоССо-3 (5ЕО ИЙУ МО: 4) was heated at 95 "С for 2 minutes and incubated at 37 "С for 1 hour to anneal with obtaining double-stranded DNA of the two synthetic DNAs defined above . The obtained double-stranded

The DNA was cleaved with the restriction enzymes Ba and Krpi, and the resulting DNA fragment was inserted into the BaP-Krpi site of the 3/5-sgtu promoter swarm to construct a plasmid swarm with the 3/6-sgtu promoter, 8 x binding site sites, i.e., the reporter site plasmids

Experimental Example 2. Construction of a plasmid for the expression of the mouse ZPYP-M terminal fragment

As a material for the construction of a plasmid for the expression of the 5PY-M end fragment, the cDNA of the mouse PP gene was first cloned.

The cDNA of the mouse ZPP gene was cloned by the method of nested PCR using the cDNA of an 11-day-old mouse fetus (Siopiesia) as a template.

As a set of primers for 12" PCR, we used 5-statatasaaAtTSIacAaASA-Z' (5EO IU MO: 5) 5B-asast ToSSATSASTTOSTTATT-3 (ZEO IU MO: 6), and as a set of primers for 227 PCR we used 5-ssaatTASsSsATaSsSTOaSTaSsTaStOaaSSA-3' ( 5EO IU MO: 7) 5B-astotTApATSsAasStTasASTTaASSOasSsSA-3 (5BO I MO: 8). The PCR reaction was carried out using Rish Tigro (Zigaiadepe) and the following added protocol. The resulting PCR product was cloned into chkKDNKZ.1 (w) (Ipmigodep), and confirmed the inserted core sequence.

Using the cDNA sequence of the mouse ZPP gene obtained as a template, as mentioned above, a partial cDNA sequence was obtained by the PCR method, in which a stop codon (TOA) was added to the 3'-terminal cDNA sequence encoding the 1-198 amino acid sequence of the mouse ZPP gene . As a set of primers we used 5-AtastastastasSstasssda-z3' (5EO IU MO: 9) 5-tsdassasSsaaaAtttaasSsSa-3 (ZEO IU MO: 10).

The RSV reaction was carried out using Ria Tigro (Zigaiadepe) and the following attached protocol.

The resulting PCR product was cloned into chKDNKZ.1 (w) (Ipmigodep), and the inserted basic sequence was confirmed.

In the same way, as mentioned above, a plasmid was constructed for the expression of the M-terminal fragment of the mouse 5pyp gene, chKDNKZ. 1/tpp-M.

Experimental Example 3. Preparation of the M-terminal fragment of the mouse Zpyp gene of a recombinant type

NEK293 cells were grown in O-MEM medium (Ipmygodep) containing 10 95 fetal bovine serum in dishes with a diameter of 10 cm, and chidNKZ.1/tZpp-M cells were introduced into the cells using

EpSsEMEEb (Rosne Arriieid Zsiepse). After that, HEK293 cells were cultured in an incubator in a carbon dioxide atmosphere at 37 "C for 24 hours, and the medium was replaced with O-MEM medium (Ipmigodep) containing 2 95 fetal bovine serum. After cultivation for 48 hours by filtration using a filter (0.22 μm) culture supernatant was obtained, which contained the M-terminal fragment of the mouse 5pi gene of the recombinant type.

Experimental Example 4. Introduction of a plasmid for c1i-1 expression and a reporter plasmid into

MIN-3T3Z cells and formation of expressing cells

Using O-MEM medium (Ipmigodep) containing 1095 fetal bovine serum, expression plasmid ChKDNKZ.1 and sii reporter plasmid (roi 3/6-sgu promoter, 8 x sii binding site), obtained by the method of Experimental Example 1, was injected MIN-3T3 cells grown in dishes with a diameter of 10 cm, with the use of RysEMeb (Kospe Arriei Zsiepse).

After cultivation for 24 hours, the cells were removed, suspended in O-MEM medium containing 10 95 fetal bovine serum, supplemented with Sepeiysip (I Te Tesppoiodie5 Ogiepiai!, Ips.) to a final concentration of 500 mg/ml, diluted to a concentration of 107 cells/ml , were placed in a 96-well plate and cultivated in an incubator in an atmosphere of carbon dioxide at 37 C to obtain a transformed cell line resistant to Sepeiysip.

The resulting transformed cell line was cultivated in a 96-well plate, the M-terminal fragment of the mouse Zpyp gene obtained in Experimental Example 3 was added, and MIN-

ZT3/sii reporter cell, which is a cell line capable of inducing the expression of luciferase.

Experimental Example 5. Evaluation of the compound

MIN-3T3 reporter cells cultured in O-MEM medium (Ipmigodep) containing 95 fetal bovine serum were placed in a 96-well transparent plate at a concentration of 1 x 102 cells/well and cultured overnight in an incubator in an atmosphere of carbon dioxide at 37 "С.

The medium was removed, the compound (50 μl) and the culture supernatant of the M-terminal fragment of the mouse Zpp gene expressing HEK293 were added (0-MEM medium contained 2 90 fetal bovine serum, 50 μl), and the cells were cultured for 48 hours in an incubator in in an atmosphere of carbon dioxide at 37 "C. Hydnesio (Rgoteda, 50 μl) was added, and the mixture was mixed, after which the luciferase activity was measured using Epmisiop (RegKkipEIteg). The degree of inhibition was calculated on the basis of the luciferase activity of the control sample without the addition of the compound, taken as 100. The results are shown in the Table below.The concentration of the compound and the degree of inhibition were analyzed using RKIZM3.00 (SgarpRad software), based on which the IC of the compound was calculated (the concentration of the compound required to achieve 50 95 of the maximum value of the degree of inhibition).

IC value of the compounds of Examples 2, 3, 9, 13, 16, 17, 22, 27, 32, A1, 43, 45, 48, 50, 51, 52, 53, 56, 69, 71, 73, 74, 79, 92, 102, 109 and 115 were not greater than 1 µM.

Table From us: tires now: now dust: pi PO KE To OO va 1111180

Experimental Example 6. Study of the antitumor activity of ip mimo

According to the description in Zavzaki, K. et al., (2006) Sapseg Ke5. 66: 4215-4222, the antitumor effect of the compound was evaluated using a murine medulloblastoma model induced by allogeneic transplantation. More precisely, a mouse with a mutant gene in the Raisnea 1 protein (line name: Risptyt'!Mrz/)) was obtained from Te Chaskbop Garogayiog and a mouse with a mutant p53Z gene (line name P5ZM4-M, nomenclature: B6.129-TgtroZit/Vgamma) was obtained from Tasopis, and a mouse phenotype Raispea 1(w/-), ro5Z3(-/-) was obtained by mating. Tumor tissue of medulloblastoma, which spontaneously arose in the cerebellum of a 7- - d-week-old mouse with Raispei 1(w/-), p53(-/-) was selected and subcutaneously transplanted into a "tolii" mouse (line name: САпМ.Сд-Рохпи "пи "/ STISTIES).

Studies of antitumor activity were carried out using a tumor transplanted by subcutaneous transplantation. The tumor formation was isolated using a 40 μm cell filter (VO

Viozsiepse5, Catal. No. 352340), the tumor suspension was obtained in 1-15 Leibowitz medium (SIVSO, Cat. No. 11415-114) in a 2-fold amount in relation to the mass of the tumor, mixed with an equivalent amount of Matrigel (VO Wiozsiepse5, Cat. No. 356237) and subcutaneously mice were transplanted in the amount of 100 μl per transplant site. Tumor diameter was measured after transplantation and when the tumor size reached 150-250 mm3, antitumor studies were initiated using 5 mice per group.

The test compound was prepared to reach a dose of 6.25 mg/kg in a 0.5 9% suspension in methylcellulose (Zpip-Eibi Spetis! So., (4Я., Cat. No. ЗМ-100), and was administered orally twice a day for 2 weeks . Tumor size was evaluated by the longer diameter and shorter diameter of the tumor measured with an electronic vernier caliper. After the start of the study, the tumor size was measured every 2 or 3 days and the degree of tumor size growth was evaluated. The tumor growth inhibitory effect of 95 95 or higher in each group was confirmed , in which the study compound was prescribed.The degree of tumor size growth under the influence of each study compound at the end of the study is shown in the following

Tables.

The extent of tumor growth and the results of significant differences in the study of each compound are shown in the Table. The degree of growth of tumor size (T/S) was calculated according to the following formula:

Growth rate (T/C) - (tumor size in the compound-injected group at the end of administration)-(tumor size in the compound-injected group at the beginning of the administration))/(tumor size in the control group at the end of the administration) )-(tumor size in the control group at the beginning of administration)) X100.

Table 4 79437177111110877117171111111111111111111111kООМ1

148331 17111100171111111111111111111kООМ1

The above results confirm that the compound of this invention exhibits an antitumor effect.

Industrial suitability

Since the compound of the present invention exhibits a potent 5-to inhibitory effect, a useful agent for the prevention or treatment of 5-to-related diseases (eg, cancer, etc.) can be obtained. In addition, since the compound of this invention also exhibits extraordinary characteristics of expression efficiency, pharmacokinetics, solubility, interaction with other pharmaceutical products, safety and stability, it is suitable as a pharmaceutical agent.

This application is based on Mo Mo applications 2008-045134 and 2008-256755 filed in Japan, the contents of which are incorporated by reference in their entirety.

LIST OF SEQUENCES

"110" Takeda Pharmaceutical Company Limited "1992. CONDENSED HETEROCYCLIC DERIVATIVE AND ITS APPLICATION "130" 091350 "150" ZRObOV-045134 "1515 2008-02-55 "150" УР2О08-256755 "1851: 2008-10-01 "1802 10 "1702 Виоп13054 meg. "B11 28 "12" DNA "cut" Artificial "rich "two PCR primer "ah 1 chaazayuyue sadossavdsissaddy 28 "2105 2 "oh 25 "va" DNA "13" Artificial "220" "vas" PCR primer. "400". 2 sesazosiys dssodsasa essay 29 "8102 3 "0112 88 "12" DEC "rez" Artificial checker" and "y?3Z" synthetic DNA for 8 x Sp-binding site "400" Z doociassov ssasssadae ssssadass asssadassa sosvdas ssadassvos 60 sadassasss adassasssa adaisne 88. "Oh and

"211" 88 "ah DNA "213" Artificial cad" "da3" synthetic DNA for 8 x Binding site "490" 4 dvadeno oayuvtsisyuv vyutsdisyuva dou osisuvayu sisyuchuya 50 estva syuda daaosos 8 -9105 5 "2115 20 "9125 DNA " 13" Artificial "De "dra" PCR primer "4005 5 siddoyuoche aisodadasa 20 "105 6 "11" 24 "2122 DNA "213" Artificial "220" "98232 PCE primer "00" 6 that dsiasises visaonse thai 24 "8102 7 " 112" 27 "2122" DAK "213" Artificial "Oh "23" PCE primer "NYU"

Chodaassai choshcheoe stdosa 27 kaiikh 8 "Ti" 78 "2122 DNA "213" Artificial "o" "P23" PCR primer

"AP V asyuiaoais adsiddasii dassossa 28 "10" 8

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Claims (19)

1. A compound represented by the formula e 2 MORE -- in 2,9 in which ring A is a 5- to 7-membered ring, optionally having a substituent(s), and the substituents are optionally bonded to each other with formation of a ring; X stands for O, 5 or ME! (B/ means a hydrogen atom or a hydrocarbon group, which optionally has a substituent(s)); ВЕ" means carbamoyl, optionally having a substituent(s); and E7 means hydroxy, optionally having a substituent(s), except for the following compounds: ho on ho. ) (c) E E E E E E somn, soMN, 5? Their A M on same as S M M o (c) M - with Y Nm E SOM, sOMmN, Z ikh he ne ach I ho he M (in) Ge! Me va Me va; nm E schu E Me SsOMmNn, SsOoMnMe With their 5 X A ho on A s on M M (c) (c) I g schu i schu E Mme7 SOMMe; сОМН, Z 8 X som on X A -- A on M M M xx o X ho E (c) and Osn» o o N schu E NM A E or its salt. 2. The compound according to claim 1, which is represented by the formula in? SCHE ra dA2 S y y t- ra M o . e (173 in which X, ELE are as defined in item 1, VAM KA are the same or different and each is a hydrogen atom or a substituent, or VAM 1 BA? are optionally bonded to each other to form 5- 7-membered ring, optionally having substituent(s), 1 "BE" means a hydrogen atom or a hydrocarbon group, optionally having a substituent(s). 3. The compound according to claim 2, which is represented by the formula e 2 X vag ho X e Z vy Y o) " in which X, ВЕ are as defined in item 1, BAV are the same or different 1 each is a hydrogen atom or a substituent , 1 E" means a hydrogen atom or a hydrocarbon group, which optionally has a substituent(s). 4, A compound according to claim 3, in which X is O, 5 or M(Ci-alkyl), ВЕ" means carbamoyl, which does not necessarily have a substituent(s), B means hydroxy, which does not necessarily have Si-alkyl, which does not necessarily "necessarily has a substituent(s), BA" means a hydrogen atom or a C. alkyl group, B" means a hydrogen atom or a C. alkyl group, and E" means a hydrogen atom or a C. alkyl group, which optionally has a substituent(s) . 5. The compound according to claim 1, which is represented by the formula е 2 оо Ме оо І (о) 4 и ; 0) in which Х, ВЕ are as defined in 1, ring B is a b-membered ring, optionally having substituent(s); 1 E" means a hydrogen atom or a hydrocarbon group, optionally having a substituent(s). b. A compound according to claim 5, in which ring B is a b-membered ring, optionally having a substituent(s), X is 0, 5 or M(Ci-alkyl), VE? means carbamoyl, optionally having a substituent(s), B means hydroxy, optionally having a C 1 alkyl, optionally having a substituent(s) 1 E" means a hydrogen atom or a C 1 alkyl, optionally having a substituent (and). 7. М-П1-(2-hydroxyethyl)piperidine-4-1l|-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-IN- pyrrolo|3,2-c|quinoline-2-carboxamide or its salt. 8. M-P-(hydroxyacetyl)piperidine-4-1l|-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-IN-pyrrolo| 3.2-s| c nolin-2-carboxamide or its salt. 9. 3-Ethoxy-b-ethyl-M-| 1-(tihydroxyacetyl)piperidine-4-17l |- 1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-IN-pyrrolo|3,2-s|pyridine- 2-carboxamide or its salt. 10. M-P1-(hydroxyacetyl)piperidin-4-yl|-1,6-dimethyl-4-oxo-5-(2-oxo-2-phenylethyl)-3-(2,2,2-trifluoroethoxy)- 4,5-dihydro-IN-pyrrolo|3,2-s|pridine-2-carboxamide or its salt. 11. 6-Ethyl-M-|1-(tihydroxyacetyl)piperidine-4-1l|-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-3-(2,2,2- trifluoroethoxy)-4,5-dihydro-IN-pyrrolo|3,2-c|pyridine-2-carboxamide or its salt. 12. Prodrugs of the compound defined in claim 1. 13. Pharmaceutical agent containing the compound according to claim 1 or its salt. 14. Pharmaceutical agent according to claim 13, which is a 5to-inhibitor. 15. The pharmaceutical agent according to claim 13, which is an agent for the prevention or treatment of cancer. 16. A method of inhibiting 5to in a mammal, according to which an effective amount of the compound according to claim 1 or its prodrug is administered to the mammal. 17. A method of preventing or treating cancer in a mammal, according to which an effective amount of the compound according to claim 1 or its prodrug is administered to the mammal. 18. Use of the compound according to claim 1 or its prodrugs for the production of a 5to-inhibitor. 19. Use of the compound according to claim 1 or its prodrugs for the production of an agent for the prevention or treatment of cancer.