KR100922486B1 - Novel, arylsusfonamide compounds for the treatment of obesity, type ii diabetes and cns-disorders - Google Patents

Novel, arylsusfonamide compounds for the treatment of obesity, type ii diabetes and cns-disorders Download PDF

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KR100922486B1
KR100922486B1 KR1020037014656A KR20037014656A KR100922486B1 KR 100922486 B1 KR100922486 B1 KR 100922486B1 KR 1020037014656 A KR1020037014656 A KR 1020037014656A KR 20037014656 A KR20037014656 A KR 20037014656A KR 100922486 B1 KR100922486 B1 KR 100922486B1
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amino
phenyl
hydrochloride
diazepane
benzenesulfonamide
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KR20040007549A (en
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칼디롤라파트리치아
브렘베르그울프
옌센아니카
요한손개리
모트앤드류
수틴로리
테이브란트얀
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바이오비트럼 에이비(피유비엘)
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Abstract

본 발명은 화학식 I 또는 화학식 II 의 치환된 비스-아릴술폰아미드 및 아릴술폰아미드 화합물에 관한 것으로서, 상리 화합물들은 비만, 제 II 형 당뇨병 및/또는 중추신경계의 장애의 예방 및 치료에 잠재적으로 유용하다. The present invention relates to substituted bis-arylsulfonamides and arylsulfonamide compounds of formula (I) or formula (II), wherein the isolation compounds are potentially useful for the prevention and treatment of obesity, type II diabetes and / or disorders of the central nervous system. .

Description

비만, 제 Ⅱ 형 당뇨병 및 ＣＮＳ 장애의 치료를 위한 신규한 아릴술폰아미드 화합물{NOVEL, ARYLSUSFONAMIDE COMPOUNDS FOR THE TREATMENT OF OBESITY, TYPE II DIABETES AND CNS-DISORDERS}Novel Arylsulfonamide Compounds for the Treatment of Obesity, Type II Diabetes and CNS DisordersNOVEL, ARYLSUSFONAMIDE COMPOUNDS FOR THE TREATMENT OF OBESITY, TYPE II DIABETES AND CNS-DISORDERS

관련 출원Related Applications

본 출원은 본원에 참고문헌으로 포함되는, 2001 년 5 월 11 일 출원한 스웨덴 출원 번호 0101660-9, 2001 년 5 월 29 일에 출원한 U.S 가출원 번호 60/294,102, 및 2001 년 5 월 29 일 출원한 U.S. 가출원 번호 60/294,132 를 우선권으로 청구한다. This application is Swedish Application No. 0101660-9, filed May 11, 2001, US Provisional Application No. 60 / 294,102, filed May 29, 2001, and May 29, 2001, which is incorporated herein by reference. One US Claim Provisional Application No. 60 / 294,132 as priority.

본 발명은 치환된 비스-아릴술폰아미드 및 아릴술폰아미드 화합물, 상기 화합물들을 함유하는 약제학적 조성물, 및 비만, 제 II 형 당뇨병 및/또는 중추신경계 장애에 연관된 의학적 상태의 예방 및 치료를 위한 상기 화합물들의 용도에 관한 것이다. The present invention provides substituted bis-arylsulfonamide and arylsulfonamide compounds, pharmaceutical compositions containing the compounds, and the compounds for the prevention and treatment of obesity, type II diabetes and / or medical conditions associated with central nervous system disorders. It is about their use.

비만은 체지방 함량의 증가로 인해, 허용되는 표준을 초과하는 과체중을 초래하는 것을 특징으로 하는 상태이다. 비만은 서구 세계에서는 가장 중요한 영양 장애이며, 모든 산업 국가에서 주요 건강 문제를 대표한다. 상기 장애는 심혈관계 질환, 소화계 질환, 순환계 질환, 암 및 제 II 형 당뇨병과 같은 질병 증가로 인한 사망율 증가를 유도한다. 수십년간 체중을 감량하는 화합물에 대한 연구가 진행되었다. 한 가지 연구는 세로토닌 수용체 서브타입의 직접적인 활성화 또는 세로토닌 재흡수의 저해에 의한 세로토닌계 시스템의 활성화였다. 그러나, 필요한 정확한 수용체 서브타입 프로파일이 공지되지 않았다. Obesity is a condition characterized by an increase in body fat content resulting in overweight exceeding an acceptable standard. Obesity is the most important nutritional disorder in the western world and represents a major health problem in all industrial countries. The disorder leads to an increase in mortality due to diseases such as cardiovascular disease, digestive system disease, circulatory disease, cancer and type II diabetes. Research has been conducted on compounds that lose weight for decades. One study was the activation of serotonin-based systems by direct activation of serotonin receptor subtypes or inhibition of serotonin reuptake. However, the exact receptor subtype profile required is not known.

말초 및 중추신경계의 주요 전달자인 세로토닌 (5-히드록시트립타민 또는 5-HT) 은 불안, 수면 조절, 공격성, 섭식 및 우울함을 포함하는 광범위한 생리적 및 병리적 기능을 조절한다. 다중 세로토닌 수용체 서브타입은 동정되어 클로닝되었다. 이들 중 하나인 5-HT6 수용체는, 1993 년에 여러 그룹에 의해 클로닝되었다 (Ruat, M. 등 (1993) Biochem. Biophys. Res. Commun.193: 268-276; Sebben, M. 등 (1994) NeuroReport 5: 2553-2557). 상기 수용체는 아데닐릴 싸이클라아제에 실제적으로 커플링되어, 클로자핀과 같은 항울제에 대한 친화성을 나타낸다. 최근에는, 5-HT6 길항제 및 5-HT6 안티센스 올리고뉴클레오티드의 래트에서의 식량 섭취 감소 효과가 보고되었다 (Bentley, J.C. 등 (1999) Br J Pharmac. Suppl. 126. P66; Bentley, J.C. 등 (1997) J. Psychopharinacol. Suppl. A64, 255). Serotonin (5-hydroxytryptamine or 5-HT), the major messenger of the peripheral and central nervous system, regulates a wide range of physiological and pathological functions including anxiety, sleep control, aggressiveness, feeding and depression. Multiple serotonin receptor subtypes have been identified and cloned. One of these 5-HT 6 receptors has been cloned by several groups in 1993 (Ruat, M. et al. (1993) Biochem. Biophys. Res. Commun. 193: 268-276; Sebben, M. et al. (1994) ) NeuroReport 5: 2553-2557). The receptor is practically coupled to adenylyl cyclase, thus exhibiting affinity for antidepressants such as clozapine. Recently, effects of reducing food intake in rats of 5-HT 6 antagonists and 5-HT 6 antisense oligonucleotides have been reported (Bentley, JC et al. (1999) Br J Pharmac. Suppl. 126. P66; Bentley, JC et al. ( 1997) J. Psychopharinacol.Suppl. A64, 255).

5-HT6 수용체에 대한 증강된 친화성 및 선택성을 가진 화합물은, 예컨대 WO 00/34242 및 문헌 [Isaac, M. 등 (2000.) 6-Bicyclopiperazillyl-1-arylsulfonylindoles and 6-Bicyclopiperidinyl-1-arylsulfonylindoles derivatives as novel, potent and selective 5-HT 6 receptor antagonists. Bioorganic & Medicinal Chemistry Letters 10: 1719-1721] 에서 동정되었다. Compounds with enhanced affinity and selectivity for 5-HT 6 receptors are described, for example, in WO 00/34242 and in Isaac, M. et al. (2000.) 6-Bicyclopiperazillyl-1-arylsulfonylindoles and 6-Bicyclopiperidinyl-1-arylsulfonylindoles derivatives as novel, potent and selective 5-HT 6 receptor antagonists . Bioorganic & Medicinal Chemistry Letters 10: 1719-1721.

발명의 개시 Disclosure of Invention

놀랍게도 화학식 I 및 II 의 화합물이 낮은 나노몰 범위에서 길항제로서 5-HT6 수용체에 대한 친화성을 나타낸다는 것을 발견했다. 본 발명에 따른 화합물 및 그의 약제학적으로 허용되는 염은 5-HT6 수용체 길항제 활성을 가지며, 비만 및 제 II 형 당뇨병의 치료 또는 예방 뿐만 아니라, 중추신경계 장애, 예컨대 불안, 우울, 공황 발작, 기억 장애, 수면 장애, 폭식 장애, 편두통, 거식증, 대식증, 강박 장애, 정신증, 알츠하이머 병 (Alzheimer's disease), 파킨슨씨 병 (Parkinson's disease), 헌팅턴씨 (Huntington's) 무도병 및/또는 정신분열증, 약물 중독, 주의력결핍 과다활동장애 (ADHD) 의 치료 또는 예방에서 잠재적인 용도의 것으로 여겨진다. It has been surprisingly found that compounds of formulas (I) and (II) exhibit affinity for the 5-HT 6 receptor as an antagonist in the low nanomolar range. The compounds according to the invention and their pharmaceutically acceptable salts have 5-HT 6 receptor antagonist activity, as well as the treatment or prevention of obesity and type II diabetes, as well as central nervous system disorders such as anxiety, depression, panic attacks, memory Disorders, sleep disorders, binge eating disorders, migraine, anorexia, bulimia, obsessive compulsive disorder, psychosis, Alzheimer's disease, Parkinson's disease, Huntington's chorea and / or schizophrenia, drug addiction, attention It is considered a potential use in the treatment or prevention of deficit hyperactivity disorder (ADHD).

정의Justice

다른 설명 또는 표시가 없으면, 명세서 및 첨부된 청구범위를 통해 하기의 정의가 적용될 것이다:Unless otherwise indicated or indicated, the following definitions will apply throughout the specification and the appended claims:

용어 "C1-6 알킬" 은 탄소수 1 내지 6 의 직쇄형 또는 분지형 알킬기를 의미한다. 상기 저급 알킬의 예에는, 메틸, 에틸, n-프로필, 이소-프로필, n-부틸, 이소-부틸, sec-부틸, t-부틸 및 직쇄형 및 분지형 사슬 펜틸 및 헥실이 포함된다. The term "C 1-6 alkyl" means a straight or branched alkyl group having 1 to 6 carbon atoms. Examples of such lower alkyls include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl and straight and branched chain pentyl and hexyl.

용어 "C1-6 알콕시" 는 탄소수 1 내지 6 의 직쇄형 또는 분지형 알콕시기를 의미한다. 상기 저급 알콕시의 예에는, 메톡시, 에톡시, n-프로폭시, 이소프로폭시, n-부톡시, 이소-부톡시, sec-부톡시, t-부톡시 및 직쇄형 및 분지형 사슬 펜톡 시 및 헥속시가 포함된다.The term "C 1-6 alkoxy" means a straight or branched alkoxy group having 1 to 6 carbon atoms. Examples of such lower alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, t-butoxy and straight and branched chain pentoxy And hexoxy.

용어 "할로겐" 은 불소, 염소, 브롬 또는 요오드를 의미한다. The term "halogen" means fluorine, chlorine, bromine or iodine.

용어 "C4-6 시클로알킬" 및 "C3-7 시클로알킬" 은, 각각 C4 내지 C6 또는 C3 내지 C7 의 고리 크기를 가진 시클릭 알킬기를 의미한다. 상기 시클로알킬기의 예에는, 시클로프로필, 시클로부틸, 시클로펜틸, 시클로헥실, 메틸시클로헥실 및 시클로헵틸이 포함된다. The terms "C 4-6 cycloalkyl" and "C 3-7 cycloalkyl" refer to cyclic alkyl groups having a ring size of C 4 to C 6 or C 3 to C 7 , respectively. Examples of the cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexyl and cycloheptyl.

화학식 I 의 화합물Compound of formula (I)

제 1 국면에서, 본 발명은 화학식 I 의 화합물 및 그의 약제학적으로 허용되는 염을 제공한다: In a first aspect, the present invention provides a compound of formula I and a pharmaceutically acceptable salt thereof:

Figure 112003042468427-pct00001
Figure 112003042468427-pct00001

[식 중, X 는 하기이며: [Wherein X is:

Figure 112003042468427-pct00002
Figure 112003042468427-pct00002

Figure 112003042468427-pct00003
Figure 112003042468427-pct00003

R1 및 R3 는 독립적으로 R 1 and R 3 are independently

(a) H (a) H

(b) C1-6 알킬, (b) C 1-6 alkyl,

(C) C1-6 알콕시, (C) C 1-6 alkoxy,

(d) 직쇄형 또는 분지형 C1-6 히드록시알킬, (d) straight or branched C 1-6 hydroxyalkyl,

(e) 직쇄형 또는 분지형 C1-6 알킬할라이드; 또는 (e) straight or branched C 1-6 alkyl halides; or

(f) 기 Ar 이며; (f) the group Ar;

Ar 은 Ar is

(a) 페닐, (a) phenyl,

(b) 1-나프틸, (b) 1-naphthyl,

(c) 2-나프틸, (c) 2-naphthyl,

(d) 벤질, (d) benzyl,

(e) 시나밀 (cinnamyl), (e) cinnamil,

(f) 5 내지 7 원의, 부분적으로 또는 완전히 포화된, 산소, 질소 및 황으로부터 선택되는 1 내지 4 개의 헤테로원자를 포함하는 복소환이거나, 또는 (f) a 5 to 7 membered, partially or fully saturated heterocycle containing 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur, or                 

(g) (f) 에서 정의된 바와 같은 복소환 2 개로 이루어진 2 환 고리계이거나, 또는 하나의 벤젠 고리 및 (f) 에서 정의된 바와 같은 하나의 복소환으로 이루어진 2 환 고리계이며; (g) a bicyclic ring system consisting of two heterocycles as defined in (f), or a bicyclic ring system consisting of one benzene ring and one heterocycle as defined in (f);

대안적으로는, R1 및 R3 은 연결되어 화학식 Ib 에서 기 (CH2)20, (CH2)40, 또는 (CH2)3-5 를 형성하며; Alternatively, R 1 and R 3 are joined to form a group (CH 2 ) 2 0, (CH 2 ) 4 0, or (CH 2 ) 3-5 in formula Ib;

임의로는, 기 Ar 가 하기로 치환되며: Optionally, the group Ar is substituted with:

(a) Y, 또는(a) Y, or

(b) 5 내지 7 원의, 부분적으로 또는 완전히 포화된, 각각 산소, 질소 또는 황으로부터 선택되는 1 내지 4 개의 헤테로원자를 포함하는 복소환이며;(b) a 5 to 7 membered, partially or fully saturated heterocycle containing 1 to 4 heteroatoms each selected from oxygen, nitrogen or sulfur;

Y 는 Y is

(a) H, (a) H,

(b) 할로겐, (b) halogen,

(c) C1-6 알킬, (c) C 1-6 alkyl,

(d) CF3, (d) CF 3 ,

(e) 히드록시, (e) hydroxy,

(f) C1-6 알콕시, (f) C 1-6 alkoxy,

(g) C1-4 알케닐; (g) C 1-4 alkenyl;

(h) 페닐; (h) phenyl;                 

(i) 페녹시, (i) phenoxy,

(j) 벤질옥시, (j) benzyloxy,

(k) 벤조일, (k) benzoyl,

(l) OCF3, (l) OCF 3 ,

(m) CN, (m) CN,

(n) 직쇄형 또는 분지형 C1-6 히드록시알킬, (n) straight or branched C 1-6 hydroxyalkyl,

(o) 직쇄형 또는 분지형 C1-6 알킬할라이드, (o) straight or branched C 1-6 alkyl halides,

(p) NH2, (p) NH 2 ,

(q) NHR6,(q) NHR 6 ,

(r) NR6R7, (r) NR 6 R 7 ,

(s) N02, (s) N0 2 ,

(t) -CONR6R7, (t) -CONR 6 R 7 ,

(u) NHS02R6,(u) NHS0 2 R 6 ,

(v) NR6COR7, (v) NR 6 COR 7 ,

(x) S02NR6R7, (x) S0 2 NR 6 R 7 ,

(z) -C(=O)R6, (z) -C (= 0) R 6 ,

(aa) -CO2R6, 또는 (aa) -CO 2 R 6 , or

(ab) S(O)nR6; 여기서, n 은 0, 1, 2 또는 3 이며; (ab) S (O) n R 6 ; Where n is 0, 1, 2 or 3;

R2 및 R4 는 독립적으로: R 2 and R 4 are independently:

(a) -SO2R1, (a) -SO 2 R 1 ,

(b) H, (b) H,

(C) C1-6 알킬, (C) C 1-6 alkyl,

(d) C1-C3 알케닐, (d) C 1 -C 3 alkenyl,

(e) C1-C3 알킬아릴, (e) C 1 -C 3 alkylaryl,

(f) Ar 로서, R1 에 대해 상기 정의된 것, (f) Ar, as defined above for R 1 ,

(g) -C(=O)R6, (g) -C (= 0) R 6 ,

(h) -C(O)NR6R7, (h) -C (O) NR 6 R 7 ,

(i) -C(S)NR6R7, (i) -C (S) NR 6 R 7 ,

(j) -CO2R6; (j) -CO 2 R 6 ;

(k) -C(S)R6; (k) -C (S) R 6 ;

(l) 직쇄형 또는 분지형 C1-6 히드록시알킬이거나, 또는 (l) straight or branched C 1-6 hydroxyalkyl, or

(m) 직쇄형 또는 분지형 C1-6 알킬할라이드이며; (m) straight or branched C 1-6 alkyl halides;

대안적으로는, R2 및 R4 는 연결되어 화학식 Ia 에서 기 (CH2)20, (CH2)40 또는 (CH2)3-5 를 형성하며;Alternatively, R 2 and R 4 are joined to form a group (CH 2 ) 2 0, (CH 2 ) 4 0 or (CH 2 ) 3-5 in formula (Ia);

R5 는 하기 화학기로 이루어지는 군으로부터 선택되며:R 5 is selected from the group consisting of:

Figure 112003042468427-pct00004
Figure 112003042468427-pct00004

R6 및 R7 는 독립적으로 하기이며:R 6 and R 7 are independently

(a) H, (a) H,

(b) C1-6 알킬, (b) C 1-6 alkyl,

(C) C3-7 시클로알킬, 또는 (C) C 3-7 cycloalkyl, or

(d) Ar 로서, R1 에 대해 상기 정의된 것; (d) Ar, as defined above for R 1 ;

대안적으로는, R6 및 R7 는 연결되어 기 (CH2)20, (CH2 )40 또는 (CH2)3-5 를 형성하며; Alternatively, R 6 and R 7 are joined to form a group (CH 2 ) 2 0, (CH 2 ) 4 0 or (CH 2 ) 3-5 ;

R8 은 R 8 is

(a) H, 또는 (a) H, or

(b) C1-6 알킬이다]. (b) C 1-6 alkyl].

화학식 I 의 바람직한 화합물은 하기의 것이다:Preferred compounds of formula I are

X 가 하기이며:X is

[화학식 Ia]Formula Ia

Figure 112003042468427-pct00005
Figure 112003042468427-pct00005

[화학식 Ib]Formula Ib

Figure 112003042468427-pct00006
Figure 112003042468427-pct00006

R1 은 R 1 is

(e) 기 Ar 이거나; 또는(e) the group Ar; or

(f) C1-6 알킬이며 (f) C 1-6 alkyl

Ar 은 Ar is

(a) 페닐, (a) phenyl,

(b) 1 -나프틸, (b) 1 -naphthyl,

(c) 2-나프틸, 또는 (c) 2-naphthyl, or

(f) 5 내지 7 원의, 부분적으로 또는 완전히 포화된, 산소, 질소 및 황으로부터 선택되는 1 내지 4 개의 헤테로원자를 포함하는 복소환이며; (f) a 5 to 7 membered, heterocyclic ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur, partially or fully saturated;

기 Ar 은 Y 로 치환되며, Y 는 Ar is substituted with Y, Y is

(a) H, (a) H,

(b) 할로겐, (b) halogen,

(C) C1-6 알킬, (C) C 1-6 alkyl,

(d) CF3, (d) CF 3 ,

(f) C1-6 알콕시, (f) C 1-6 alkoxy,

(g) C1-4 알케닐; (g) C 1-4 alkenyl;

(h) 페닐; (h) phenyl;

(l) OCF3, 또는 (l) OCF 3 , or

(n) 직쇄형 또는 분지형 C1-6 히드록시알킬이며; (n) straight or branched C 1-6 hydroxyalkyl;

기

Figure 112003042468427-pct00007
는 페닐 고리에서 2 위치 또는 3 위치에 결합하며; group
Figure 112003042468427-pct00007
Is bonded at the 2 or 3 position in the phenyl ring;

R2 및 R4 는 독립적으로 R 2 and R 4 are independently

(a) H (a) H

(b) C1-3 알킬, 특히 메틸 또는 에틸이거나 (b) C 1-3 alkyl, in particular methyl or ethyl

(c) -SO2R1 이거나; 또는 (c) -SO 2 R 1 ; or

(d) 연결되어 기 (CH2)40 를 형성하며(d) linked to form a group (CH 2 ) 4 0

R5 는 하기 화학기로 이루어지는 군으로부터 선택되며:R 5 is selected from the group consisting of:

Figure 112003042468427-pct00008
Figure 112003042468427-pct00008

[식 중, R8 은[Wherein R 8 is

(a) H, 또는 (a) H, or

(b) C1-6 알킬, 특히 메틸이다]. (b) C 1-6 alkyl, especially methyl].

R6 및 R7 은 독립적으로 R 6 and R 7 are independently

(a) H, (a) H,

(b) C1-6 알킬, (b) C 1-6 alkyl,

(c) C3-7 시클로알킬, 또는 (c) C 3-7 cycloalkyl, or

(d) Ar 이다. (d) Ar.                 

N-[2-[에틸(페닐술포닐)아미노]-4-(4-메틸-1-피페라지닐)페닐] 벤젠술폰아미드 히드로클로라이드, N- [2- [ethyl (phenylsulfonyl) amino] -4- (4-methyl-1-piperazinyl) phenyl] benzenesulfonamide hydrochloride,

3-플루오로-N-[2-{[(3-플루오로페닐)술포닐]아미노}-4-(4-메틸-1-피페라지닐)페닐]벤젠술폰아미드 히드로클로라이드, 3-fluoro-N- [2-{[(3-fluorophenyl) sulfonyl] amino} -4- (4-methyl-1-piperazinyl) phenyl] benzenesulfonamide hydrochloride,

N-{4-(4-메틸-1-피페라지닐)-2-[(8-퀴놀리닐술포닐)아미노]페닐}-8-퀴놀린술폰아미드 히드로클로라이드, N- {4- (4-methyl-1-piperazinyl) -2-[(8-quinolinylsulfonyl) amino] phenyl} -8-quinolinesulfonamide hydrochloride,

4-메틸-N-{4-(4-메틸-1-피페라지닐)-2-[(메틸술포닐)아미노]페닐]벤젠술폰아미드 히드로클로라이드, 4-methyl-N- {4- (4-methyl-1-piperazinyl) -2-[(methylsulfonyl) amino] phenyl] benzenesulfonamide hydrochloride,

N-{4-(1-피페라지닐)-2-[(페닐술포닐)아미노]페닐}-1-나프탈렌술폰아미드 히드로클로라이드, N- {4- (1-piperazinyl) -2-[(phenylsulfonyl) amino] phenyl} -1-naphthalenesulfonamide hydrochloride,

N-[2-[(페닐술포닐)아미노]-4-(1-피페라지닐)페닐]-8-퀴놀린술폰아미드 히드로클로라이드,N- [2-[(phenylsulfonyl) amino] -4- (1-piperazinyl) phenyl] -8-quinolinesulfonamide hydrochloride,

2-메틸-N-[2-[(페닐술포닐)아미노]-4-(1-피페라지닐)페닐]벤젠술폰아미드 히드로클로라이드,2-methyl-N- [2-[(phenylsulfonyl) amino] -4- (1-piperazinyl) phenyl] benzenesulfonamide hydrochloride,

4-부톡시-N-[2-[(페닐술포닐)아미노]-4-(1-피페라지닐)페닐]벤젠술폰아미드 히드로클로라이드,4-butoxy-N- [2-[(phenylsulfonyl) amino] -4- (1-piperazinyl) phenyl] benzenesulfonamide hydrochloride,

5-플루오로-2-메틸-N-[2-[(페닐술포닐)아미노]-4-(1-피페라지닐)페닐]벤젠술폰아미드, 5-fluoro-2-methyl-N- [2-[(phenylsulfonyl) amino] -4- (1-piperazinyl) phenyl] benzenesulfonamide,

2-메톡시-4-메틸-N-[2-[(페닐술포닐)아미노]-4-(1-피페라지닐)페닐]벤젠술폰아미드 히드로클로라이드, 2-methoxy-4-methyl-N- [2-[(phenylsulfonyl) amino] -4- (1-piperazinyl) phenyl] benzenesulfonamide hydrochloride,                 

N-{4-(1,4-디아제판-1-일)-2-[(페닐술포닐)아미노]페닐}벤젠술폰아미드 히드로클로라이드, N- {4- (1,4-diazepane-1-yl) -2-[(phenylsulfonyl) amino] phenyl} benzenesulfonamide hydrochloride,

N-{5-(1,4-디아제판-1-일)-2-[(페닐술포닐)아미노]페닐}-N-에틸벤젠술폰아미드 히드로클로라이드, N- {5- (1,4-diazepane-1-yl) -2-[(phenylsulfonyl) amino] phenyl} -N-ethylbenzenesulfonamide hydrochloride,

N-{4-(1,4-디아제판-1-일)-2-[(메틸술포닐)아미노]페닐}-2-나프탈렌술폰아미드 히드로클로라이드, N- {4- (1,4-diazepane-1-yl) -2-[(methylsulfonyl) amino] phenyl} -2-naphthalenesulfonamide hydrochloride,

N-{4-(1,4-디아제판-1-일)-2-[메틸(메틸술포닐)아미노]페닐}벤젠술폰아미드 히드로클로라이드, N- {4- (1,4-diazepane-1-yl) -2- [methyl (methylsulfonyl) amino] phenyl} benzenesulfonamide hydrochloride,

N-{4-(1,4-디아제판-1-일)-2-[(메틸술포닐)아미노]페닐}-1-나프탈렌술폰아미드 히드로클로라이드, N- {4- (1,4-diazepane-1-yl) -2-[(methylsulfonyl) amino] phenyl} -1-naphthalenesulfonamide hydrochloride,

N-{4-(1,4-디아제판-1-일)-2-[(메틸술포닐)아미노]페닐}-2-나프탈렌술폰아미드 히드로클로라이드, N- {4- (1,4-diazepane-1-yl) -2-[(methylsulfonyl) amino] phenyl} -2-naphthalenesulfonamide hydrochloride,

N-{4-(1,4-디아제판-1-일)-2-[메틸(메틸술포닐)아미노]페닐}-1-나프탈렌술폰아미드 히드로클로라이드, N- {4- (1,4-diazepane-1-yl) -2- [methyl (methylsulfonyl) amino] phenyl} -1-naphthalenesulfonamide hydrochloride,

N-{4-(1,4-디아제판-1-일)-2-[(페닐술포닐)아미노]페닐}-8-퀴놀린술폰아미드 히드로클로라이드, N- {4- (1,4-diazepane-1-yl) -2-[(phenylsulfonyl) amino] phenyl} -8-quinolinesulfonamide hydrochloride,

N-{4-(1,4-디아제판-1-일)-2-[(페닐술포닐)아미노]페닐]-2,4,6-트리메틸벤젠술폰아미드 히드로클로라이드, N- {4- (1,4-diazepane-1-yl) -2-[(phenylsulfonyl) amino] phenyl] -2,4,6-trimethylbenzenesulfonamide hydrochloride,

N-{4-(1,4-디아제판-1-일)-2-[(페닐술포닐)아미노]페닐}-4-메틸벤젠술폰아미드 히드로클로라이드, N- {4- (1,4-diazepane-1-yl) -2-[(phenylsulfonyl) amino] phenyl} -4-methylbenzenesulfonamide hydrochloride,                 

N-{4-(1,4-디아제판-1-일)-2-[(페닐술포닐)아미노]페닐}-5-플루오로-2-메틸벤젠술폰아미드 히드로클로라이드, N- {4- (1,4-diazepane-1-yl) -2-[(phenylsulfonyl) amino] phenyl} -5-fluoro-2-methylbenzenesulfonamide hydrochloride,

N-{5-(1,4-디아제판-1-일)-2-[메틸(페닐술포닐)아미노]페닐}-4-메틸벤젠술폰아미드 히드로클로라이드, N- {5- (1,4-diazepane-1-yl) -2- [methyl (phenylsulfonyl) amino] phenyl} -4-methylbenzenesulfonamide hydrochloride,

3-아미노-4-(1,4-디아제판-1-일)-N-(2-메톡시페닐)벤젠술폰아미드 히드로클로라이드, 3-amino-4- (1,4-diazepane-1-yl) -N- (2-methoxyphenyl) benzenesulfonamide hydrochloride,

3-아미노-N-(3-클로로페닐)-4-(1,4-디아제판-1-일)벤젠술폰아미드 히드로클로라이드, 3-amino-N- (3-chlorophenyl) -4- (1,4-diazepan-1-yl) benzenesulfonamide hydrochloride,

3-아미노-N-(2-클로로페닐)-4-(1,4-디아제판-1-일)벤젠술폰아미드 히드로클로라이드, 3-amino-N- (2-chlorophenyl) -4- (1,4-diazepan-1-yl) benzenesulfonamide hydrochloride,

3-아미노-4-(4-메틸-1,4-디아제판-1-일)-N-페닐벤젠술폰아미드 히드로클로라이드, 3-amino-4- (4-methyl-1,4-diazepan-1-yl) -N-phenylbenzenesulfonamide hydrochloride,

3-아미노-N-(2-메톡시페닐)-4-(1-피페라지닐)벤젠술폰아미드 히드로클로라이드, 3-amino-N- (2-methoxyphenyl) -4- (1-piperazinyl) benzenesulfonamide hydrochloride,

2-[1,4]디아제판-1-일-5-(3,4-디히드로-1H-이소퀴놀린-2-술포닐)-아닐린 디히드로클로라이드 히드로클로라이드, 2- [1,4] diazepan-1-yl-5- (3,4-dihydro-1H-isoquinoline-2-sulfonyl) -aniline dihydrochloride hydrochloride,

3-아미노-2-클로로-N-나프탈렌-1-일-4-피페라진-1-일-벤젠술폰아미드, 히드로클로라이드 히드로클로라이드. 3-Amino-2-chloro-N-naphthalen-1-yl-4-piperazin-1-yl-benzenesulfonamide, hydrochloride hydrochloride.                 

Figure 112008080077431-pct00174
Figure 112008080077431-pct00174

Figure 112008080077431-pct00175
Figure 112008080077431-pct00175

Figure 112008080077431-pct00176
Figure 112008080077431-pct00176

Figure 112003042468427-pct00012
Figure 112003042468427-pct00012

Figure 112008080077431-pct00177
Figure 112008080077431-pct00177

Figure 112008080077431-pct00178
Figure 112008080077431-pct00178

Figure 112008080077431-pct00179
Figure 112008080077431-pct00179

Figure 112008080077431-pct00180
Figure 112008080077431-pct00180

화학식 II 의 화합물Compound of formula II

또다른 국면에서, 본 발명은 화학식 II 의 화합물 및 그의 약제학적으로 허용되는 염을 제공한다:In another aspect, the present invention provides a compound of Formula II and pharmaceutically acceptable salts thereof:

Figure 112003042468427-pct00017
Figure 112003042468427-pct00017

[식 중, [In the meal,

R9, R12 및 R14 는 H 이거나; 또는R 9 , R 12 and R 14 are H; or

R9, R12 및 R14 중 2 개가 H 이며; 남는 R9, R12 및 R14 는 Two of R 9 , R 12 and R 14 are H; The remaining R 9 , R 12 and R 14

(a) -NH2, (a) -NH 2 ,

(b) -NHR6, (b) -NHR 6 ,

(c) -NR6R7, (c) -NR 6 R 7 ,

(d) -N(CO)R6,(d) -N (CO) R 6 ,

(e) -N(CS)R6 또는 (e) -N (CS) R 6 or

(f) -NO2 이며;(f) -NO 2 ;

R10 및 R11 은 제 1 항에서의 화학식 I 에서 정의된 기 R3 또는 기 R1 이며; R 10 and R 11 are groups R 3 or group R 1 as defined in formula (I) in claim 1 ;

R13 은R 13 is

(a) 호모피페라진, (a) homopiperazine,

(b) 메틸호모피페라진, 또는(b) methyl homopiperazine, or

(c) 화학식 I 에서 정의된 기 R5 이며, 여기서 R8 은 화학식 I 에서와 같이 정의되며; (c) a group R 5 as defined in formula I, wherein R 8 is defined as in formula I;

Y 는 화학식 I 에서와 같이 정의된다.Y is defined as in formula (I).

화학식 II 의 바람직한 화합물은 하기의 것이다:Preferred compounds of formula II are:

R13 은R 13 is

(a) 호모피페라진, (a) homopiperazine,

(b) 메틸호모피페라진, 또는 (b) methyl homopiperazine, or                 

(c) 하기로부터 선택되는 기 R5 이며:(c) a group R 5 selected from:

Figure 112003042468427-pct00018
Figure 112003042468427-pct00018

R8 은R 8 is

(a) H, 또는 (a) H, or

(b) C1-6 알킬, 특히 메틸이다. (b) C 1-6 alkyl, especially methyl.

Figure 112008080077431-pct00181
Figure 112008080077431-pct00181

Figure 112003042468427-pct00020
Figure 112003042468427-pct00020

Figure 112003042468427-pct00021
Figure 112003042468427-pct00021

Figure 112003042468427-pct00022
Figure 112003042468427-pct00022

Figure 112003042468427-pct00023
Figure 112003042468427-pct00023

Figure 112008080077431-pct00182
Figure 112008080077431-pct00182

Figure 112008080077431-pct00183
Figure 112008080077431-pct00183

Figure 112003042468427-pct00026
Figure 112003042468427-pct00026

표 안의 화합물들은 달리 언급하면 히드로클로라이드 염이다. The compounds in the table are hydrochloride salts, if stated otherwise.

제조 방법Manufacturing method

2 개의 술포닐기를 가진 본 발명의 화합물은 반응식 1, 2 및 3 에 개요된 방법에 따라 제조했다. Compounds of the present invention having two sulfonyl groups were prepared according to the methods outlined in Schemes 1, 2 and 3.                 

Figure 112003042468427-pct00027
Figure 112003042468427-pct00027

Figure 112003042468427-pct00028
Figure 112003042468427-pct00028

Figure 112003042468427-pct00029
Figure 112003042468427-pct00029

공정 조건에 따라, 화학식 I 의 최종 생성물이 중성 또는 염 형태로 수득된다. 유리된 염기 및 이들 최종 생성물의 염은 모두 본 발명의 범위에 포함된다. Depending on the process conditions, the final product of formula I is obtained in neutral or salt form. Free bases and salts of these final products are all within the scope of this invention.                 

신규한 화합물의 산 부가염은, 알칼리와 같은 염기성 시약을 사용하거나 또는 이온 교환에 의해 당 분야에 공지된 방법으로 유리된 염기로 변환될 수 있다. 수득한 유리된 염기는 또한 유기산 또는 무기산과 염을 형성할 수 있다.Acid addition salts of the novel compounds can be converted to the free base using basic reagents such as alkalis or by ion exchange in a manner known in the art. The free base obtained can also form salts with organic or inorganic acids.

산부가염의 제조에서, 바람직하게는 치료적으로 허용가능한 염을 형성하는 산을 사용한다. 상기 산의 예는, 히드로할로겐산, 황산, 인산, 질산, 지방족, 지환족, 방향족 또는 복소환 카르복실 또는 술폰산, 예컨대 포름산, 아세트산, 프로피온산, 숙신산, 글리콜산, 락트산, 말산, 타르타르산, 시트르산, 아스코르브산, 말레산, 히드록시말레산, 피루브산, p-히드록시벤조산, 엠본산, 메탄술폰산, 에탄술폰산, 히드록시에탄술폰산, 할로겐벤젠술폰산, 톨루엔술폰산, 만델산 또는 나프탈렌술폰산이다. In the preparation of acid addition salts, acids which preferably form therapeutically acceptable salts are used. Examples of such acids include hydrohalogenic acid, sulfuric acid, phosphoric acid, nitric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, Ascorbic acid, maleic acid, hydroxymaleic acid, pyruvic acid, p-hydroxybenzoic acid, embonic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, halogenbenzenesulfonic acid, toluenesulfonic acid, mandelic acid or naphthalenesulfonic acid.

명세서 및 첨부된 청구범위를 통해, 주어진 화학식 또는 명칭은 모든 입체 이성질체 및 광학 이성질체, 및 존재하는 경우엔 이들의 라세미체를 포함한다. 모든 가능한 부분입체이성질체 형태 (순수한 거울상이성질체, 호변체, 라세미 혼합물 및 두 거울상이성질체의 비균등 혼합물) 가 본 발명의 범위에 포함된다. 상기 화합물들은 또한 시스- 또는 트란스-, E- 또는 Z- 이중결합 이성질체 형태로서 존재할 수 있다. 모든 이성질체 형태가 포함된다. Throughout the specification and the appended claims, the formulas or names given include all stereoisomers and optical isomers, and, if present, racemates thereof. All possible diastereomeric forms (pure enantiomers, tautomers, racemic mixtures and non-uniform mixtures of two enantiomers) are included within the scope of the present invention. The compounds may also exist in cis- or trans-, E- or Z- double bond isomeric forms. All isomeric forms are included.

약제학적 제형물Pharmaceutical Formulations

약제학적 제형물은 일반적으로 활성 물질 또는 약제학적으로 허용되는 그의 염과, 통상적인 약제학적 부형제를 혼합하여 제조한다. 제형물은 또한 과립화, 가압, 미세캡슐화, 스프레이 코팅 등과 같은 공지된 방법으로 제조될 수 있다. Pharmaceutical formulations are generally prepared by mixing the active substance or pharmaceutically acceptable salts thereof with conventional pharmaceutical excipients. The formulations can also be prepared by known methods such as granulation, pressurization, microencapsulation, spray coating and the like.                 

본 발명은 비만 또는 제 II 형 당뇨병의 치료 방법에 관한 것이다. 상기 방법에는, 유효량의 상기 화학식 I 또는 화학식 II 의 하나 이상의 화합물을 상기 치료가 필요한 포유류 대상 (예를 들어, 인간) 에게 투여하는 것을 포함한다. 또한, 본 발명의 범위 내에는 5-HT6 수용체 활성의 조절 (예를 들어, 저해) 방법이 있다. 상기 방법에는, 유효량의 상기 화학식 I 또는 화학식 II 의 화합물을 상기 치료가 필요한 포유류에게 투여하는 것이 포함된다.The present invention relates to a method of treating obesity or type II diabetes. The method includes administering an effective amount of one or more compounds of Formula I or Formula II to a mammalian subject (eg, a human) in need of such treatment. Also within the scope of the present invention is a method of modulating (eg, inhibiting) 5-HT 6 receptor activity. The method includes administering an effective amount of the compound of Formula I or Formula II to the mammal in need of such treatment.

"유효량" 은 처리된 대상에서 치료 효과를 나타내는 양을 의미한다. 치료 효과는 실증적이거나 (즉, 특정 시험 또는 마커로 측정 가능함) 또는 주관적 (즉, 대상체가 효과의 표시 또는 느낌을 제공함) 일 수 있다. 임상 용도를 위해, 본 발명의 화합물은, 경구용, 좌제용, 비경구용 또는 기타 투여 양식을 위한 약제학적 제형물로 제형화된다. 일반적으로 활성 화합물의 양은 제제의 0.1 - 95 중량%, 비경구용으로 바람직하게는 제제의 0.2 내지 20 중량%, 경구 투여용으로 바람직하게는 1 내지 50 중량% 이다. "Effective amount" means an amount that produces a therapeutic effect in a treated subject. The therapeutic effect may be empirical (ie, measurable with a particular test or marker) or subjective (ie, the subject provides an indication or feeling of effect). For clinical use, the compounds of the present invention are formulated in pharmaceutical formulations for oral, suppository, parenteral or other dosage forms. Generally the amount of active compound is from 0.1 to 95% by weight of the formulation, preferably from 0.2 to 20% by weight of the formulation, preferably from 1 to 50% by weight for oral administration.

활성 물질의 전형적인 1 일 투여량은 넓은 범위 내에서 가변적이며, 예컨대 각 환자의 개인적인 필요조건 및 투여 경로와 같은 각종 인자에 의존적이다. 일반적으로, 경구 및 비경구 투여량은 활성 물질 5 내지 1000 mg/1 일, 바람직하게는 50 내지 150 mg/1 일이다.Typical daily dosages of active substances vary within wide limits, depending on various factors such as the individual requirements and route of administration of each patient. Generally, oral and parenteral dosages are from 5 to 1000 mg / 1 day of active substance, preferably from 50 to 150 mg / 1 day.

하기 구체적인 실시예는 단지 설명으로서 해석되는 것이며, 임의로 본 발명의 나머지 부분을 한정하는 것이 아니다. 추가적인 언급없이도, 당 분야의 숙련 가는 본원의 기재를 바탕으로 본 발명을 그의 가장 완전한 범위까지 이용할 수 있다. 본원에 인용된 모든 공보는 모두 본원에 참고 문헌으로 포함된다.The following specific examples are to be construed as illustrative only and do not arbitrarily limit the remainder of the invention. Without further mention, those skilled in the art can use the present invention to its fullest extent based on the description herein. All publications cited herein are hereby incorporated by reference.

하기 실시예에서, 제조된 화합물의 구조는 표준 분광법 및 원소 분석 및/또는 고해상도 MS 로 확인했다. NMR 데이타는 JEOL JNM-EX 270, Bruker 400 DPX 또는 Bruker DRX 500 분광계 상에서 수득했다. IR 스펙트럼은 Perkin Elmer SPECTRUM 1000 FT-IR 분광계 상에서 수득했다. 고해상도 MS 는 Micromass LCT 분광계 상에서 수득했다. 원소 분석은 Mikro Kemi AB Uppsala Sweden 에 의해 수행했다. 제시된 경우 융점은 Buchi 또는 Gallenkamp 융점 장치 상에서 수득하고, 보정되지 않았다. In the examples below, the structures of the prepared compounds were confirmed by standard spectroscopy and elemental analysis and / or high resolution MS. NMR data were obtained on a JEOL JNM-EX 270, Bruker 400 DPX or Bruker DRX 500 spectrometer. IR spectra were obtained on a Perkin Elmer SPECTRUM 1000 FT-IR spectrometer. High resolution MS was obtained on a Micromass LCT spectrometer. Elemental analysis was performed by Mikro Kemi AB Uppsala Sweden. Melting points, where indicated, were obtained on a Buchi or Gallenkamp melting point apparatus and were not corrected.

반응식 1, 방법 2 (R = Boc) 에 따른 합성 Synthesis according to Scheme 1, Method 2 (R = Boc)

중간체 1 Intermediate 1

N-에틸-5-플루오로-2-니트로아닐린의 합성.Synthesis of N-ethyl-5-fluoro-2-nitroaniline .

2,4-디플루오로-1-니트로벤젠 (0.50 g, 0.003 mmol), 에틸아민 히드로클로라이드 (0.49 g, 0.006 mmol), K2CO3 (1.66 g, 0.012 mmol) 의 아세토니트릴 (30 mL) 중 현탁액을 실온에서 16 시간 동안 교반한 후 여과했다. 여과액을 농축하여, 소량의 CHCl3 에 용해했다. 95:5 의 펜탄/디에틸 에테르를 용출액으로 사용한 실리 카 상의 칼럼 크로마토그래피로 0.45 g 의 황색 고체를 수득했다. Acetonitrile (30 mL) of 2,4-difluoro-1-nitrobenzene (0.50 g, 0.003 mmol), ethylamine hydrochloride (0.49 g, 0.006 mmol), K 2 CO 3 (1.66 g, 0.012 mmol) The suspension was stirred at rt for 16 h and then filtered. The filtrate was concentrated and dissolved in a small amount of CHCl 3 . Column chromatography on silica using 95: 5 pentane / diethyl ether as eluent gave 0.45 g of a yellow solid.

Figure 112003042468427-pct00030
Figure 112003042468427-pct00030

중간체 2 Intermediate 2

N-에틸-2-니트로-5-(1-피페라지닐)아닐린의 합성. Synthesis of N-ethyl-2-nitro-5- (1-piperazinyl) aniline .

N-에틸-5-플루오로-2-니트로아닐린 (1.5 g, 8.12 mmol), 피페라진 (0.979 g, 11.37 mmol), K2CO3 (3.36 g, 24.3 mmol) 의 DMF (40 mL) 중 현탁액을 전자레인지에서 100 W 로 1 분 동안 가열했다. 반응 혼합물을 냉각시킨 후, 100 W 에서 추가로 1 분 동안 가열했다. 상기 과정을 5 회 반복했다. 현탁액을 여과한 후, 농축했다. 미정제 오일을 9:1:0.4% 의 CHCl3/MeOH/NH3 를 용출액으로 사용한 실리카 상의 플래쉬 크로마토그래피로 정제하여 1.53 g (75%) 의 황색 고체를 수득했다. Suspension of N-ethyl-5-fluoro-2-nitroaniline (1.5 g, 8.12 mmol), piperazine (0.979 g, 11.37 mmol), K 2 CO 3 (3.36 g, 24.3 mmol) in DMF (40 mL) Heated at 100 W for 1 minute in a microwave. The reaction mixture was cooled down and then heated at 100 W for a further 1 minute. The process was repeated five times. The suspension was filtered and then concentrated. The crude oil was purified by flash chromatography on silica using 9: 1: 0.4% CHCl 3 / MeOH / NH 3 as eluent to yield 1.53 g (75%) of a yellow solid.

Figure 112003042468427-pct00031
Figure 112003042468427-pct00031

중간체 3Intermediate 3

tert-부틸 4-[3-(에틸아미노)-4-니트로페닐]-1-피페라진카르복실레이트의 합 성Synthesis of tert-butyl 4- [3- (ethylamino) -4-nitrophenyl] -1-piperazinecarboxylate

N-에틸-2-니트로-5-(1-피페라지닐)아닐린 (1.020 g, 4.075 mmol) 및 NaOH (0.39 g, 2.45 mmol) 의 THF:H2O (64 mL, 1:1) 중 용액에 디-tert-부틸디카르보네이트 (2.67 g, 12.2 mmol) 의 5 mL THF 중 용액을 첨가했다. 용액을 실온에서 16 시간 동안 교반했다. 혼합물을 1 N HCl 로 중화했다. 휘발물질을 진공 하에 제거하여 1.4 g 의 미정제 물질을 수득했다 (98%). A solution of N-ethyl-2-nitro-5- (1-piperazinyl) aniline (1.020 g, 4.075 mmol) and NaOH (0.39 g, 2.45 mmol) in THF: H 2 O (64 mL, 1: 1) To a solution of di-tert-butyldicarbonate (2.67 g, 12.2 mmol) in 5 mL THF was added. The solution was stirred at rt for 16 h. The mixture was neutralized with 1 N HCl. The volatiles were removed under vacuum to afford 1.4 g of crude material (98%).

Figure 112003042468427-pct00032
Figure 112003042468427-pct00032

중간체 4 Intermediate 4

tert-부틸 4-[4-아미노-3-(에틸아미노)페닐]-1-피페라진카르복실레이트의 합성. Synthesis of tert-Butyl 4- [4-amino-3- (ethylamino) phenyl] -1-piperazinecarboxylate .

tert-부틸 4-[3-(에틸아미노)-4-니트로페닐]-1-피페라진카르복실레이트 (1.028 g, 2.93 mmol) 의 40 mL EtOH:THF (4:1) 용매계 중 용액에, 라니-Ni (1 mL 의 EtOH 현탁액) 을 첨가한 후, 히드라진 수화물 (0.734 g, 14.67 mmol) 을 첨가했다. 혼합물을 3 시간 동안 세게 교반한 후, 물로 침투된 셀라이트 패드를 통해 여과했다. 여과액을 농축한 후, 9:1:0.4% 의 CHCl3/MeOH/NH3 을 용출액으로 사용한 실리카 상의 칼럼 크로마토그래피로 정제하여 0.877 g (93%) 의 적색 오일을 수득했다. 오일은 즉시 후속 단계에서 사용했다. HPLC 순도 > 90 %; MS (posEl) m/z = 320 (M+); To a solution in 40 mL EtOH: THF (4: 1) solvent system of tert-butyl 4- [3- (ethylamino) -4-nitrophenyl] -1-piperazinecarboxylate (1.028 g, 2.93 mmol), Raney-Ni (1 mL of EtOH suspension) was added followed by hydrazine hydrate (0.734 g, 14.67 mmol). The mixture was stirred vigorously for 3 hours and then filtered through a pad of celite penetrated with water. The filtrate was concentrated and purified by column chromatography on silica using 9: 1: 0.4% CHCl 3 / MeOH / NH 3 as eluent to yield 0.877 g (93%) of red oil. The oil was used immediately in the subsequent step. HPLC purity>90%; MS (posEl) m / z = 320 (M + );

방법 1, 반응식 1: 술포닐화의 일반 (R1 = Me)Method 1, Scheme 1: General of Sulfonylation (R1 = Me)

중간체 5 Intermediate 5

N-에틸-5-(4-메틸-1-피페라지닐)-2-니트로아닐린의 합성 (방법 1, 반응식 1)Synthesis of N-ethyl-5- (4-methyl-1-piperazinyl) -2-nitroaniline (Method 1, Scheme 1)

N-에틸 (4-메틸-1-피페라지닐)-2-니트로아닐린을, 2,4-디플루오로-1-니트로벤젠 및 메틸피페라진으로부터, N-에틸-2-니트로-5-(1-피페라지닐)아닐린에 대해 기재된 것과 동일한 방법을 사용하여 제조함으로써 황색 고체로서 수득했다 (99 %). N-ethyl (4-methyl-1-piperazinyl) -2-nitroaniline was prepared from N, ethyl-2-nitro-5- (2,4-difluoro-1-nitrobenzene and methylpiperazine. Obtained as a yellow solid by preparation using the same method as described for 1-piperazinyl) aniline (99%).

Figure 112003042468427-pct00033
Figure 112003042468427-pct00033

중간체 6 Intermediate 6

N-2-에틸-4-(4-메틸-1-피페라지닐)-1,2-벤젠디아민의 합성 (방법 1, 반응식 1) Synthesis of N-2-ethyl-4- (4-methyl-1-piperazinyl) -1,2-benzenediamine (Method 1, Scheme 1)

N-에틸-5-(4-메틸-1-피페라지닐)-2-니트로아닐린을, 라니-Ni 을 사용해 tert-부틸 4-[4-아미노-3-(에틸아미노)페닐]-1-피페라진카르복실레이트의 합성에 대해 상기에 기재된 바와 같이 환원하여, N-2-에틸-4-(4-메틸-1-피페라지닐)-1,2-벤젠디아민 (수율 > 90%) 을 적색 오일로서 수득했다. 생성물은 산화에 매우 민감하므로, 후속 단계에서 즉시 사용했다. HPLC 순도 > 90 %; MS (posEl) m/z = 234 (M+); N-ethyl-5- (4-methyl-1-piperazinyl) -2-nitroaniline with tert-butyl 4- [4-amino-3- (ethylamino) phenyl] -1- using Raney-Ni Reduction as described above for the synthesis of piperazinecarboxylate yielded N-2-ethyl-4- (4-methyl-1-piperazinyl) -1,2-benzenediamine (yield> 90%). Obtained as a red oil. The product was very sensitive to oxidation and was used immediately in the subsequent step. HPLC purity>90%; MS (posEl) m / z = 234 (M + );

실시예 1 Example 1                 

N-[2-{에틸[(3-플루오로페닐)술포닐]아미노}-4-(4-메틸-1-피페라지닐)페닐]-3-플루오로벤젠술폰아미드 히드로클로라이드 (방법 1, 반응식 1)N- [2- {ethyl [(3-fluorophenyl) sulfonyl] amino} -4- (4-methyl-1-piperazinyl) phenyl] -3-fluorobenzenesulfonamide hydrochloride (method 1, Scheme 1)

아민-N-2-에틸-4-(4-메틸-1-피페라지닐)-1,2-벤젠디아민 (0.200 g, 0.853 mmol) 및 피리딘 (0.48 mL, 5.97 mmol) 의 CH2Cl2 (8 mL) 중 용액에, 3-플루오로벤젠술포닐 클로라이드 (249 mg, 1.28 mmol) 의 CH2Cl2 (2 mL) 중 용액을 첨가했다. 혼합물을 실온에서 16 시간 동안 교반했다. CH2Cl2 (10 mL) 을 첨가하고, 혼합물을 포화 NaHCO3 수용액으로 세척했다. 유기층을 Na2SO4 상에서 건조시키고, 여과하고 농축했다. 칼럼 크로마토그래피 (Al203, EtOAc/MeOH 9.5:0.5) 에 의한 정제로 2 가지 생성물을 수득했다. 제 1 분획은 110 mg 의 N-[2-{에틸[(3-플루오로페닐)술포닐]아미노}-4-(4-메틸-1-피페라지닐)페닐]-3-플루오로벤젠술폰아미드 히드로클로라이드를 함유했다. 제 2 분획은 100 mg 의 N-[2-(에틸아미노)-4-(4-메틸-1-피페라지닐)페닐]-3-플루오로벤젠술폰아미드 히드로클로라이드를 함유했다. 두 생성물을 모두 HCl 염으로 전환시켰다. CH 2 Cl 2 of amine-N-2-ethyl-4- (4-methyl-1-piperazinyl) -1,2-benzenediamine (0.200 g, 0.853 mmol) and pyridine (0.48 mL, 5.97 mmol) ( 8 mL) was added a solution of 3-fluorobenzenesulfonyl chloride (249 mg, 1.28 mmol) in CH 2 Cl 2 (2 mL). The mixture was stirred at rt for 16 h. CH 2 Cl 2 (10 mL) was added and the mixture was washed with saturated aqueous NaHCO 3 solution. The organic layer was dried over Na 2 SO 4 , filtered and concentrated. Purification by column chromatography (Al 2 0 3 , EtOAc / MeOH 9.5: 0.5) gave two products. The first fraction is 110 mg of N- [2- {ethyl [(3-fluorophenyl) sulfonyl] amino} -4- (4-methyl-1-piperazinyl) phenyl] -3-fluorobenzenesulphone Contains amide hydrochloride. The second fraction contained 100 mg of N- [2- (ethylamino) -4- (4-methyl-1-piperazinyl) phenyl] -3-fluorobenzenesulfonamide hydrochloride. Both products were converted to HCl salts.

N-[2-{에틸[(3-플루오로페닐)술포닐]아미노}-4-(4-메틸-1-피페라지닐)페닐]- 3-플루오로벤젠술폰아미드 히드로클로라이드: N- [2- {ethyl [(3-fluorophenyl) sulfonyl] amino} -4- (4-methyl-1-piperazinyl) phenyl] -3-fluorobenzenesulfonamide hydrochloride:

Figure 112003042468427-pct00034
Figure 112003042468427-pct00034

실시예 2 Example 2

N-[2-[에틸(페닐술포닐)아미노]-4-(4-메틸-1-피페라지닐)페닐]벤젠술폰아미드 히드로클로라이드 (반응식 1, 방법 1)N- [2- [ethyl (phenylsulfonyl) amino] -4- (4-methyl-1-piperazinyl) phenyl] benzenesulfonamide hydrochloride (Scheme 1, method 1)

N-[2-[에틸(페닐술포닐)아미노]-4-(4-메틸-1-피페라지닐)페닐] 벤젠술폰아미드 히드로클로라이드를 반응식 1 에 기재된 바와 같이 제조했다. N-2-에틸-4-(4-메틸-1-피페라지닐)-1,2-벤젠디아민 및 페닐술포닐 클로라이드로부터의 술포닐화를 방법 1 에서와 같이 수행했다. 크로마토그래피 (SiO2, 클로로포름:메탄올:NH3 9:1:0.4%) 에 의한 정제 후, MeOH 로 연화하여 68 mg (15% 수율) 의 유리된 염기를 수득해 그의 HCl-염으로 전환했다. N- [2- [ethyl (phenylsulfonyl) amino] -4- (4-methyl-1-piperazinyl) phenyl] benzenesulfonamide hydrochloride was prepared as described in Scheme 1. Sulfonylation from N-2-ethyl-4- (4-methyl-1-piperazinyl) -1,2-benzenediamine and phenylsulfonyl chloride was carried out as in Method 1. After purification by chromatography (SiO 2 , chloroform: methanol: NH 3 9: 1: 0.4%), it was triturated with MeOH to give 68 mg (15% yield) of the free base to convert to its HCl-salt.

Figure 112003042468427-pct00035
Figure 112003042468427-pct00035

실시예 3 Example 3

3-플루오로-N-[2-{[(3-플루오로페닐)술포닐]아미노)-4-(4-메틸-1-피페라지닐)페닐]벤젠술폰아미드 히드로클로라이드 (반응식 3)3-fluoro-N- [2-{[(3-fluorophenyl) sulfonyl] amino) -4- (4-methyl-1-piperazinyl) phenyl] benzenesulfonamide hydrochloride (Scheme 3)

2-아미노-5-(4-메틸-1-피페라지닐)아닐린의 합성. 2-니트로-3-클로로아닐린 (4.47g, 25.9 mmol), 메틸피페라진 (3.1 g, 31 mmol) 및 K2CO3 (5.41 g, 39 mmol) 의 아세토니트릴 중 혼합물을 70℃ 에서 48 시간 동안 교반했다. 혼합물을 여과하고, 칼럼 크로마토그래피 (SiO2, CH2Cl2/MeOH/헵탄/NH3 :1:5 ×0.2 %) 으로 정제하여, 1.6 g 의 생성물 (미반응 출발 물질은 분리했다) 을 수득했다: 1H-NMR δ7.66 - 7.45 (m, 5H), 6.78 (d, 1H), 6.62 (d, 1H), 6.50 (dd, 1H), 3.39 - 3.35 (m, 4H), 3.02 - 2.99 (m, 4H); MS (posES-FIA) m/z 333.0 (M+ + H). 생성물 (1.06 g, 4.49 mmol) 을 EtOH:THF (4:1) 에 용해했다. 라니-Ni 및 히드라진 (1.12 mL, 22 mmol) 을 첨가했다. 황색이 없어질 때까지 반응물을 실온에서 3 시간 동안 교반했다. 젖은 셀라이트 (Celite) 패드를 통해 여과한 후, 용매를 제거하여, 0.802 g 의 2-아미노-5-(4-메틸-1-피페라지닐)아닐린을 수득해, 추가적인 정제없이 후속 단계에서 사용했다. 3-플루오로벤젠술포닐 클로라이드 (0.133 g, 0.68 mmol) 를 2-아미노-5-(4-메틸-1-피페라지닐)아닐린 (0.141 g, 0.68 mmol) 및 피리딘 (514 mL, 6.39 mmol) 의 CH2Cl2 중 용액에 첨가했다. 1 시간 후, 혼합물을 수성 NaHCO3 (10 %) 로 세척하고, 건조 (MgSO4) 하고, 용매를 제거했다. 크로마토그래피 (SiO2, CH2Cl2/메탄올/헵탄, 4:1:5) 에 의한 정제로 3-플루오로-N-[2-아미노-4-(4-메틸-1-피페라지닐)-페닐]벤젠술폰아미드 (0.140 g, 57 %) 를 수득했다. MS (pos ES-FIA) m/z = 실측치: 365.2, 계산치: 364.14; 분석치 (C17H22ClFN4O2Sㆍ3H20) C, H, N, S. 반응물은 소량의 비스술포닐화 화합물 3-플루오로-N-[2-{[(3-플루오로페닐)술포닐]아미노}-4-(4-메틸-1-피페라지닐)-페닐]벤젠술폰아미드 (0.010 g, 3 %) 를 생성했다. 분석 전에 생성물을 그의 HCl-염으로 전환했다; Synthesis of 2-amino-5- (4-methyl-1-piperazinyl) aniline . A mixture of 2-nitro-3-chloroaniline (4.47 g, 25.9 mmol), methylpiperazine (3.1 g, 31 mmol) and K 2 CO 3 (5.41 g, 39 mmol) in acetonitrile at 70 ° C. for 48 hours Stirred. The mixture was filtered and purified by column chromatography (SiO 2 , CH 2 Cl 2 / MeOH / heptane / NH 3 : 1: 5 × 0.2%) to afford 1.6 g of product (unreacted starting material was separated). It had: 1 H-NMR δ7.66 - 7.45 (m, 5H), 6.78 (d, 1H), 6.62 (d, 1H), 6.50 (dd, 1H), 3.39 - 3.35 (m, 4H), 3.02 - 2.99 (m, 4H); MS (posES-FIA) m / z 333.0 (M + + H). The product (1.06 g, 4.49 mmol) was dissolved in EtOH: THF (4: 1). Raney-Ni and hydrazine (1.12 mL, 22 mmol) were added. The reaction was stirred at room temperature for 3 hours until yellow disappeared. After filtration through a wet Celite pad, the solvent was removed to yield 0.802 g of 2-amino-5- (4-methyl-1-piperazinyl) aniline, which was used in the next step without further purification. did. 3-fluorobenzenesulfonyl chloride (0.133 g, 0.68 mmol) to 2-amino-5- (4-methyl-1-piperazinyl) aniline (0.141 g, 0.68 mmol) and pyridine (514 mL, 6.39 mmol) To a solution in CH 2 Cl 2 . After 1 h, the mixture was washed with aqueous NaHCO 3 (10%), dried (MgSO 4 ) and the solvent removed. Purification by chromatography (SiO 2 , CH 2 Cl 2 / methanol / heptane, 4: 1: 5) 3-fluoro-N- [2-amino-4- (4-methyl-1-piperazinyl) -Phenyl] benzenesulfonamide (0.140 g, 57%) was obtained. MS (pos ES-FIA) m / z = found: 365.2, calculated: 364.14; Analytical value (C 17 H 22 ClFN 4 O 2 S.3H 2 0) C, H, N, S. The reactants were reacted with a small amount of bissulfonylated compound 3-fluoro-N- [2-{[(3-fluorophenyl ) Sulfonyl] amino} -4- (4-methyl-1-piperazinyl) -phenyl] benzenesulfonamide (0.010 g, 3%). The product was converted to its HCl-salt before analysis;

Figure 112003042468427-pct00036
Figure 112003042468427-pct00036

실시예 4 Example 4

N-{4-(4-메틸-1-피페라지닐)-2-[(8-퀴놀리닐술포닐)아미노]페닐}-8-퀴놀린술폰아미드 히드로클로라이드 (반응식 3) N- {4- (4-methyl-1-piperazinyl) -2-[(8-quinolinylsulfonyl) amino] phenyl} -8-quinolinesulfonamide hydrochloride (Scheme 3)

8-퀴놀린술포닐 클로라이드 (0.185 g, O.81 mmol) 을 2-아미노-5-(4-메틸-1-피페라지닐)아닐린 (0.168 g, O.81 mmol) 및 피리딘 (514 mL, 6.39 mmol) 의 CH2Cl2 중 용액에 첨가했다. 1 시간 후, 실온에서 혼합물을 수성 NaHCO3 (10 %) 로 세척하고, 건조 (MgSO4) 하고, 용매를 제거했다. 크로마토그래피 (SiO2, CH2Cl 2/MeOH/헵탄, 4:1:5) 에 의한 정제로 N-2-아미노-4-(4-메틸-1-피페라지닐)-]-페닐-8-퀴놀린술폰아미드 (0.110 g, 35 %) 를 수득했다: MS (posES-FIA) m/z = 실측치: 384.2, 계산치 383.48; 분석치 (C19H22ClN502Sㆍ3H20) C, H, N, S; 및 소량의 비스-술포닐화 N-{(4-(4-메틸-1-피페라지닐)-2-[(8-퀴놀리닐술포닐)아미노]페닐}-8-퀴놀린술폰아미드 (0.070 g, 15 %) 를 수득했다. 분석 전에 생성물을 그의 HCl 염으로 전환시 켰다; 8-Quinolinesulfonyl chloride (0.185 g, O.81 mmol) to 2-amino-5- (4-methyl-1-piperazinyl) aniline (0.168 g, O.81 mmol) and pyridine (514 mL, 6.39 mmol) was added to the solution in CH 2 Cl 2 . After 1 h, the mixture was washed with aqueous NaHCO 3 (10%) at room temperature, dried (MgSO 4 ) and the solvent removed. Purification by chromatography (SiO 2 , CH 2 Cl 2 / MeOH / heptane, 4: 1: 5) N-2-amino-4- (4-methyl-1-piperazinyl)-]-phenyl-8 -Quinolinesulfonamide (0.110 g, 35%) was obtained: MS (posES-FIA) m / z = found: 384.2, calculated 383.48; Anal (C 19 H 22 ClN 5 0 2 S.3H 2 0) C, H, N, S; And a small amount of bis-sulfonylated N-{(4- (4-methyl-1-piperazinyl) -2-[(8-quinolinylsulfonyl) amino] phenyl} -8-quinolinesulfonamide (0.070 g, 15%) The product was converted to its HCl salt prior to analysis;

Figure 112003042468427-pct00037
Figure 112003042468427-pct00037

반응식 2 에 따른 합성Synthesis according to Scheme 2

반응식 2, 방법 3: 일반 R1 = MeScheme 2, Method 3: General R1 = Me

중간체 7 Intermediate 7

N-(5-플루오로-2-니트로페닐)벤젠술폰아미드의 합성 (반응식 2, 방법 3) Synthesis of N- (5-fluoro-2-nitrophenyl) benzenesulfonamide (Scheme 2, Method 3)

벤젠술폰아미드 (3.14 g, 20 mmol) 를 DMF (100 mL) 에 용해시키고, NaH (오일 중 60%, 40 mmol, 1.60 g) 를 첨가했다. 기체 발생이 정지할 때까지 반응물을 교반했다. 2,4-디플루오로니트로벤젠 (18 mmol, 2.9 g, 2 mL) 을 첨가하고, 반응 혼합물을 밤새 35℃ 에서 교반했다. 반응 혼합물에 HCl (1 M 수용액, 100 mL) 를 붓고, 톨루엔 (25 mL ×5) 으로 추출했다. 유기상을 건조 (MgSO4) 시키고 농축하여, EtOH 로부터 재결정하여 제 1 수확물인 3.75 g 의 황색 고체를 수득했다. 제 2 수득물 0.20 g 를 EtOH 잔류물로부터 수집했다. 수율 3.95 g, 13.3 mmol (74%). Benzenesulfonamide (3.14 g, 20 mmol) was dissolved in DMF (100 mL) and NaH (60% in oil, 40 mmol, 1.60 g) was added. The reaction was stirred until gas evolution ceased. 2,4-difluoronitrobenzene (18 mmol, 2.9 g, 2 mL) was added and the reaction mixture was stirred at 35 ° C. overnight. HCl (1 M aqueous solution, 100 mL) was poured into the reaction mixture, and the mixture was extracted with toluene (25 mL × 5). The organic phase was dried (MgSO 4 ) and concentrated to recrystallize from EtOH to afford 3.75 g of a yellow solid as the first crop. 0.20 g of the second yield was collected from the EtOH residue. Yield 3.95 g, 13.3 mmol (74%).

Figure 112003042468427-pct00038
Figure 112003042468427-pct00038

중간체 8 Intermediate 8

N-[5-(4-메틸-1-피페라지닐)-2-니트로페닐]벤젠술폰아미드의 합성 (반응식 2, 방법 3)Synthesis of N- [5- (4-methyl-1-piperazinyl) -2-nitrophenyl] benzenesulfonamide (Scheme 2, Method 3)

N-(5-플루오로-2-니트로페닐)벤젠술폰아미드 (2 ×0.50 g, 1.688 mmol) 에 N-메틸-피페라진 (2 ×4.65 g, 45.6 mmol) 를 처리하고, 2 개의 파이렉스관에 넣어 밀봉했다. 각각의 관을 LabWell MW-10 전자레인지 오븐에서 5O W 로 2 분 동안 넣었다. 반응 혼합물을 배합하고, 0.5 M NaOH (aq) 를 붓고, CH2Cl2 로 추출하고, 건조 (MgSO4) 하고 농축하여, 황색 고체 0.99 g (2.63 mmol) 를 78% 의 수율로 수득했다. 분석치 (C17H20N404S) C, H, N, S; N- (5-fluoro-2-nitrophenyl) benzenesulfonamide (2 × 0.50 g, 1.688 mmol) was treated with N-methyl-piperazine (2 × 4.65 g, 45.6 mmol), and the two pyrex tubes were Put into sealed. Each tube was placed at 50 W for 2 minutes in a LabWell MW-10 microwave oven. The reaction mixture was combined, 0.5 M NaOH (aq) was poured out, extracted with CH 2 Cl 2 , dried (MgSO 4 ) and concentrated to give 0.99 g (2.63 mmol) of a yellow solid in 78% yield. Anal (C 17 H 20 N 4 0 4 S) C, H, N, S;

Figure 112003042468427-pct00039
Figure 112003042468427-pct00039

실시예 5 Example 5

N-[2-클로로-4-({4-메틸-1-피페라지닐)-2-[(페닐술포닐)아미노]아닐리노}술포닐)페닐]아세트아미드 히드로클로라이드 (반응식 2, 방법 3)N- [2-chloro-4-({4-methyl-1-piperazinyl) -2-[(phenylsulfonyl) amino] anilino} sulfonyl) phenyl] acetamide hydrochloride (Scheme 2, method 3 )

N-[5-(4-메틸-1-피페라지닐)-2-니트로페닐]벤젠술폰아미드 (0.600 g, 1.59 mmol) 를 THF (20 mL) 에 용해한 후, 라니-Ni (0.322 g, 에탄올 중) 및 히드라진 수화물 (0.100 g, 2.0 mmol) 을 첨가했다. 반응 혼합물을 1 시간 동안 교반하고, 셀라이트 (Celite) 를 통해 여과하고 농축했다. 잔사를 피리딘 (12 mL) 에 용해하고, 12 부로 등분했다. 한 부에 3-클로로-4-N-아세트아미도벤젠술포닐클로라이드 (52 mg, 0.20 mmol) 를 첨가했다. 반응 혼합물을 밤새 교반하고, 석유 에테르를 부어 침전을 형성하도록 하여, 원심분리로 수집했다. 침전물은 칼럼 크로마토그래피 (SiO2, CH2Cl2/MeOH 95:5 내지 9:1) 로 정제했다. 순수한 생성물을 MeOH 에 용해하고, HCl/디에틸 에테르를 처리하여 9.6 mg 을 수득했다 (12% 수율).

Figure 112003042468427-pct00040
N- [5- (4-methyl-1-piperazinyl) -2-nitrophenyl] benzenesulfonamide (0.600 g, 1.59 mmol) was dissolved in THF (20 mL), followed by Raney-Ni (0.322 g, ethanol). Heavy) and hydrazine hydrate (0.100 g, 2.0 mmol) were added. The reaction mixture was stirred for 1 hour, filtered through Celite and concentrated. The residue was dissolved in pyridine (12 mL) and divided into 12 parts. To one part was added 3-chloro-4-N-acetamidobenzenesulfonylchloride (52 mg, 0.20 mmol). The reaction mixture was stirred overnight and poured by petroleum ether to form a precipitate, which was collected by centrifugation. The precipitate was purified by column chromatography (SiO 2 , CH 2 Cl 2 / MeOH 95: 5 to 9: 1). The pure product was dissolved in MeOH and treated with HCl / diethyl ether to give 9.6 mg (12% yield).
Figure 112003042468427-pct00040

실시예 6 Example 6

3,4-디메톡시-N-{4-(4-메틸-1-피페라지닐)-2-[(페닐술포닐)아미노]페닐}벤젠술폰아미드 히드로클로라이드 (반응식 2, 방법 3) 3,4-dimethoxy-N- {4- (4-methyl-1-piperazinyl) -2-[(phenylsulfonyl) amino] phenyl} benzenesulfonamide hydrochloride (Scheme 2, method 3)

N-[5-(4-메틸-1-피페라지닐)-2-니트로페닐]벤젠술폰아미드 (0.600 g, 1.59 mmol) 를 THF (20 mL) 에 용해한 후, 라니-Ni (에탄올 중 0.322 g) 및 히드라진 수화물 (0.100 g, 2.0 mmol) 을 첨가했다. 반응 혼합물을 1 시간 동안 교반하고, 셀라이트로 여과하고 농축했다. 잔사를 피리딘 (12 mL) 에 용해하고 12 부로 등분했다. 한 부에 3,4-디메톡시-벤젠술포닐클로라이드 (47 mg, 0.20 mmol) 를 첨가했다. 반응 혼합물을 밤새 교반하고, 석유 에테르를 부어 침전을 형성해, 원심분리로 수집했다. 침전을 칼럼 크로마토그래피 (SiO2, CH2Cl12/MeOH 95:5 내지 9:1) 로 정제했다. 순수한 생성물을 MeOH 에 용해시키고, HCl/디에틸 에테르로 처리하여, 34.5 mg 를 수득했다 (45% 수율). N- [5- (4-methyl-1-piperazinyl) -2-nitrophenyl] benzenesulfonamide (0.600 g, 1.59 mmol) was dissolved in THF (20 mL) and then Rani-Ni (0.322 g in ethanol) ) And hydrazine hydrate (0.100 g, 2.0 mmol) were added. The reaction mixture was stirred for 1 h, filtered through celite and concentrated. The residue was dissolved in pyridine (12 mL) and divided into 12 parts. To one part was added 3,4-dimethoxy-benzenesulfonylchloride (47 mg, 0.20 mmol). The reaction mixture was stirred overnight, pour petroleum ether to form a precipitate and collected by centrifugation. The precipitate was purified by column chromatography (SiO 2 , CH 2 Cl 12 / MeOH 95: 5 to 9: 1). The pure product was dissolved in MeOH and treated with HCl / diethyl ether to give 34.5 mg (45% yield).

Figure 112003042468427-pct00041
Figure 112003042468427-pct00041

실시예 7 Example 7

3-메톡시-4-메틸-N-{4-(4-메틸-1-피페라지닐)-2-[(페닐술포닐)아미노]페닐}벤젠술폰아미드 히드로클로라이드 (반응식 2, 방법 3)3-methoxy-4-methyl-N- {4- (4-methyl-1-piperazinyl) -2-[(phenylsulfonyl) amino] phenyl} benzenesulfonamide hydrochloride (Scheme 2, method 3)

N-[5-(4-메틸-1-피페라지닐)-2-니트로페닐]벤젠술폰아미드 (0.600 g, 1.59 mmol) 를 THF (20 mL) 에 용해한 후, 라니-Ni (에탄올 중 0.322 g) 및 히드라진 수화물 (0.100 g, 2.0 mmol) 을 첨가했다. 반응 혼합물을 1 시간 동안 교반하고, 셀라이트로 여과하고 농축했다. 잔사를 피리딘 (12 mL) 에 용해하고 12 부로 등분했다. 한 부에 2-메톡시-4-메틸벤젠술포닐클로라이드 (44 mg, 0.20 mmol) 를 첨가했다. 반응 혼합물을 밤새 교반하고, 석유 에테르를 부어 침전을 형성해, 원심분리로 수집했다. 침전을 칼럼 크로마토그래피 (SiO2, CH2Cl2/Me0H 95:5 내지 9:1) 로 정제했다. 순수한 생성물을 MeOH 에 용해하고, HCl/디에틸 에테르로 처리해 21 mg 을 수득했다 (28% 수율). N- [5- (4-methyl-1-piperazinyl) -2-nitrophenyl] benzenesulfonamide (0.600 g, 1.59 mmol) was dissolved in THF (20 mL) and then Rani-Ni (0.322 g in ethanol) ) And hydrazine hydrate (0.100 g, 2.0 mmol) were added. The reaction mixture was stirred for 1 h, filtered through celite and concentrated. The residue was dissolved in pyridine (12 mL) and divided into 12 parts. To one part was added 2-methoxy-4-methylbenzenesulfonylchloride (44 mg, 0.20 mmol). The reaction mixture was stirred overnight, pour petroleum ether to form a precipitate and collected by centrifugation. The precipitate was purified by column chromatography (SiO 2 , CH 2 Cl 2 / Me0H 95: 5 to 9: 1). The pure product was dissolved in MeOH and treated with HCl / diethyl ether to give 21 mg (28% yield).

Figure 112003042468427-pct00042
Figure 112003042468427-pct00042

중간체 9 Intermediate 9

N-(5-플루오로-2-니트로페닐)메탄술폰아미드의 합성 (반응식 2, 방법 3)Synthesis of N- (5-fluoro-2-nitrophenyl) methanesulfonamide (Scheme 2, Method 3)

메틸술폰아미드 (2.421 g, 25.4 mmol) 를 DMF (100 mL) 에 용해하고, NaH (오일 중 60%, 1.00 g, 25 mmol) 를 첨가했다. 반응 혼합물을 1 시간 동안 교반하고, 교반된 2,4-디플루오로니트로벤젠 (4.372 g, 27.5 mmol) 의 DMF (20 mL) 중 용액에 첨가했다. 반응 혼합물을 2 시간 동안 교반하고, 식염수 및 1 M HCl 혼합물 (1:1) 을 첨가하고, 톨루엔으로 추출했다. 유기상을 건조 (MgSO4) 하고, 농축하여 고체를 수득해, 톨루엔/석유 에테르로부터 결정화했다. 플라스크를 비우고, 일부 물질을 없에, 1.32 g, 5.64 mmol 를 22% 의 수율로 수득했다. Methylsulfonamide (2.421 g, 25.4 mmol) was dissolved in DMF (100 mL) and NaH (60% in oil, 1.00 g, 25 mmol) was added. The reaction mixture was stirred for 1 hour and added to a solution of stirred 2,4-difluoronitrobenzene (4.372 g, 27.5 mmol) in DMF (20 mL). The reaction mixture was stirred for 2 hours, brine and 1 M HCl mixture (1: 1) were added and extracted with toluene. The organic phase was dried (MgSO 4 ) and concentrated to give a solid which crystallized from toluene / petroleum ether. The flask was emptied and, without some material, 1.32 g, 5.64 mmol in 22% yield.

Figure 112003042468427-pct00043
Figure 112003042468427-pct00043

분석치 (C7H7FN204S), C, H, N, S. Anal (C 7 H 7 FN 2 0 4 S), C, H, N, S.

중간체 10 Intermediate 10                 

N-[5-(4-메틸-1-피페라지닐)-2-니트로페닐]-메탄술폰아미드의 합성 (반응식 2, 방법 3). Synthesis of N- [5- (4-methyl-1-piperazinyl) -2-nitrophenyl] -methanesulfonamide (Scheme 2, method 3) .

N-(5-플루오로-2-니트로페닐)메탄술폰아미드 (1.33 g, 5.68 mmol) 를 DMF (1O mL) 에 용해하고, N-메틸피페라진 (2.00 g, 20 mmol) 을 첨가했다. 반응 혼합물을 20℃ 에서 1 시간 동안 교반한 후, 열풍기로 5 분 동안 가열하여, DMF 의 융점 (150℃) 에 도달한 후, 다시 1 시간 동안 교반했다. 이어서, 반응 혼합물을 식염수에 붓고, 톨루엔 (10 mL ×2), EtOAc (20 mL ×2) 및 CH2Cl2 (20 mL ×2) 로 추출하고, NaHCO3 를 수성상에 첨가한 후, 수성상을 CH2Cl2 (20 mL ×2) 로 추출했다. 유기상을 배합하고, 건조 (MgSO4) 시키고 농축하여, 반고체를 수득했다. EtOH 를 첨가하고, 밤새 정치시킨 후, 여과하여 1.503 g (4.78 mmol) 을 84 % 의 수율로 수득했다.

Figure 112003042468427-pct00044
N- (5-fluoro-2-nitrophenyl) methanesulfonamide (1.33 g, 5.68 mmol) was dissolved in DMF (10 mL) and N-methylpiperazine (2.00 g, 20 mmol) was added. The reaction mixture was stirred at 20 ° C. for 1 hour, then heated with a hot air fan for 5 minutes to reach the melting point (150 ° C.) of DMF, and then stirred for 1 hour. The reaction mixture is then poured into brine, extracted with toluene (10 mL × 2), EtOAc (20 mL × 2) and CH 2 Cl 2 (20 mL × 2) and NaHCO 3 is added to the aqueous phase, followed by water The phase was extracted with CH 2 Cl 2 (20 mL × 2). The organic phases were combined, dried (MgSO 4 ) and concentrated to give a semisolid. EtOH was added and allowed to stand overnight, followed by filtration to give 1.503 g (4.78 mmol) in 84% yield.
Figure 112003042468427-pct00044

분석치 (C12H18N404S), C, H, N, S. Anal (C 12 H 18 N 4 0 4 S), C, H, N, S.

실시예 8 Example 8

4-메틸-N-{4-(4-메틸-1-피페라지닐)-2-[(메틸술포닐)아미노]페닐}벤젠술폰아미드 히드로클로라이드 (반응식 2, 방법 3) 4-methyl-N- {4- (4-methyl-1-piperazinyl) -2-[(methylsulfonyl) amino] phenyl} benzenesulfonamide hydrochloride (Scheme 2, method 3)

N-[5-(4-메틸-1-피페라지닐)-2-니트로페닐]-메탄술폰아미드 (0.45 g, 1.43 mmol) 를 THF (10 mL) 에 용해시킨 후, 라니-Ni (에탄올 중 O.15 g) 및 히드라진 수화물 (78 mg, 1.56 mmol) 을 첨가했다. 반응물을 1 시간 동안 교반했다. 또다른 분취물인 히드라진 수화물 (20 ㎕) 을 첨가하고, 반응물을 다시 1 시간 교반 하고, 셀라이트로 여과하고 농축하여, 0.42 g 를 수득해, 추가적인 정제없이 후속 단계에서 사용했다. 물질을 DMF (10 mL) 에 용해하고, 3 부로 등분했다. 한 부에 p-톨루엔 술포닐 클로라이드 (0.095 g, 0.5 mmol) 를 첨가하고, 반응물을 1 시간 동안 교반하고, 석유 에테르/아세톤 (30 mL/10 mL) 의 혼합물에 부어 침전을 수득했다. 추가적인 생성물을 용액 중에서 발견하여, 침전에 첨가했다. 생성물을 크로마토그래피 (SiO2, CH2Cl2)/MeOH 9:1) 로 분리하여 0.063 g 을 28% 의 수율로 수득했다. N- [5- (4-methyl-1-piperazinyl) -2-nitrophenyl] -methanesulfonamide (0.45 g, 1.43 mmol) was dissolved in THF (10 mL) and then Rani-Ni (in ethanol). 0.1 g) and hydrazine hydrate (78 mg, 1.56 mmol) were added. The reaction was stirred for 1 hour. Another aliquot, hydrazine hydrate (20 μl) was added and the reaction stirred again for 1 h, filtered through celite and concentrated to give 0.42 g, which was used in the next step without further purification. The material was dissolved in DMF (10 mL) and divided into 3 parts. To one part p-toluene sulfonyl chloride (0.095 g, 0.5 mmol) was added and the reaction stirred for 1 hour and poured into a mixture of petroleum ether / acetone (30 mL / 10 mL) to give a precipitate. Additional product was found in solution and added to the precipitate. The product was separated by chromatography (SiO 2 , CH 2 Cl 2 ) / MeOH 9: 1) to give 0.063 g in 28% yield.

Figure 112003042468427-pct00045
Figure 112003042468427-pct00045

실시예 9 Example 9

3,4-디메톡시-N-{4-(4-메틸-1-피페라지닐)-2-[(메틸술포닐)아미노]페닐}벤젠술폰아미드 히드로클로라이드 (반응식 2, 방법 3)3,4-dimethoxy-N- {4- (4-methyl-1-piperazinyl) -2-[(methylsulfonyl) amino] phenyl} benzenesulfonamide hydrochloride (Scheme 2, method 3)

N-[5-(4-메틸-1-피페라지닐)-2-니트로페닐]-메탄술폰아미드 (0.45 g, 1.43 mmol) 를 THF (1O mL) 에 용해하고, 라니-Ni (에탄올 중 0.15 g) 및 히드라진 수화물 (78 mg, 1.56 mmol) 을 첨가하고, 반응물을 1 시간 동안 교반했다. 추가적인 히드라진 수화물 (20 ㎕) 을 첨가하고, 반응물을 1 시간 더 교반하고, 셀라이트로 여과하고 농축하여, 0.42 g 의 생성물을 추가의 여과없이 사용했다. 물질을 DMF (10 mL) 에 용해하고, 3 부로 등분했다. 한 부에 3,4 디메톡시벤젠술포닐클로라이드 (O.118 g, 0.5 mmol) 을 첨가하고, 반응물을 1 시간 동안 교반하고, 석유 에테르/아세톤 (30 mL/10 mL) 의 혼합물에 부어 침전을 형성했다. 추가적인 생성물 을 용액 중에 발견하여 침전에 첨가했다. 생성물을 크로마토그래피 (SiO2, CH2Cl2)/MeOH 9:1) 로 분리하여 0.064 g (26% 수율) 를 수득했다. N- [5- (4-methyl-1-piperazinyl) -2-nitrophenyl] -methanesulfonamide (0.45 g, 1.43 mmol) is dissolved in THF (10 mL) and Raney-Ni (0.15 in ethanol) g) and hydrazine hydrate (78 mg, 1.56 mmol) were added and the reaction stirred for 1 hour. Additional hydrazine hydrate (20 μl) was added and the reaction stirred for 1 h more, filtered through celite and concentrated to use 0.42 g of product without further filtration. The material was dissolved in DMF (10 mL) and divided into 3 parts. To one part 3,4 dimethoxybenzenesulfonylchloride (O.118 g, 0.5 mmol) is added, the reaction is stirred for 1 hour and poured into a mixture of petroleum ether / acetone (30 mL / 10 mL) to precipitate Formed. Additional product was found in solution and added to the precipitate. The product was separated by chromatography (SiO 2 , CH 2 Cl 2 ) / MeOH 9: 1) to give 0.064 g (26% yield).

Figure 112003042468427-pct00046
Figure 112003042468427-pct00046

실시예 10 Example 10

3-시아노-N-{4-(4-메틸-1-피페라지닐)-2-[(메틸술포닐)아미노]페닐}벤젠술폰아미드 히드로클로라이드 (반응식 2, 방법 3)3-cyano-N- {4- (4-methyl-1-piperazinyl) -2-[(methylsulfonyl) amino] phenyl} benzenesulfonamide hydrochloride (Scheme 2, method 3)

N-[5-(4-메틸-1-피페라지닐)-2-니트로페닐]-메탄술폰아미드 (0.45 g, 1.43 mmol) 를 THF (10 mL) 에 용해시키고, 라니-Ni (에탄올 중 O.15 g) 를 첨가한 후 히드라진 수화물 (78 mg, 1.56 mmol) 를 첨가해, 반응물을 1 시간 동안 교반했다. 추가적인 히드라진 수화물 (20 ㎕) 을 첨가하고, 반응물을 1 시간 더 교반하고, 셀라이트로 여과하고 농축하여 0.42 g 의 생성물을 수득해, 추가의 정제없이 사용했다. 물질을 DMF (1O mL) 에 용해하고, 3 부로 등분했다. 한 부에 3-시아노벤젠술포닐클로라이드 (O.101 g, 0.5 mmol) 를 첨가하고, 반응물을 1 시간 동안 교반하고, 석유 에테르/아세테이트 (30 mL/10 mL) 혼합물에 부어 침전을 형성했다. 추가적인 생성물을 용액 중에 발견하여 침전에 배합했다. 생성물을 크로마토그래피 (SiO2, CH4Cl2/Me0H 9:1) 로 분리해, 0.0301 g (13% 수율) 를 수득했다. N- [5- (4-methyl-1-piperazinyl) -2-nitrophenyl] -methanesulfonamide (0.45 g, 1.43 mmol) is dissolved in THF (10 mL) and Raney-Ni (O in ethanol .15 g) was added followed by hydrazine hydrate (78 mg, 1.56 mmol), and the reaction was stirred for 1 hour. Additional hydrazine hydrate (20 μl) was added and the reaction stirred for an additional hour, filtered through celite and concentrated to yield 0.42 g of product, which was used without further purification. The material was dissolved in DMF (10 mL) and divided into 3 parts. To one part 3-cyanobenzenesulfonylchloride (O.101 g, 0.5 mmol) was added and the reaction stirred for 1 hour and poured into a petroleum ether / acetate (30 mL / 10 mL) mixture to form a precipitate. . Additional product was found in solution and combined for precipitation. The product was separated by chromatography (SiO 2 , CH 4 Cl 2 / Me0H 9: 1) to give 0.0301 g (13% yield).

Figure 112003042468427-pct00047
Figure 112003042468427-pct00047

반응식 2, 방법 4: 일반 R1 = H Scheme 2, Method 4: General R1 = H

N-(2-아미노-5-(4-boc-1-피페라지닐)-페닐)-벤젠술폰아미드 N- (2-Amino-5- (4-boc-1-piperazinyl) -phenyl) -benzenesulfonamide

N-(2-니트로-3-플루오로페닐)-벤젠술폰아미드 (4.68 g, 15.7 mmol), Boc-피페라진 (3.5 g, 18.9 mmol) 및 K2CO3 (3.8 g, 27.8 mmol) 의 DMF 중 혼합물을 70℃ 에서 24 시간 동안 교반했다. 혼합물을 여과하고, 칼럼 크로마토그래피 (SiO2, CH2Cl2/Me0H/헵탄/NH3 4:1:5:0.2 %) 로 정제하여 2.0 g 의 원하는 생성물을 수득했다. DMF of N- (2-nitro-3-fluorophenyl) -benzenesulfonamide (4.68 g, 15.7 mmol), Boc-piperazine (3.5 g, 18.9 mmol) and K 2 CO 3 (3.8 g, 27.8 mmol) The middle mixture was stirred at 70 ° C. for 24 hours. The mixture was filtered and purified by column chromatography (SiO 2 , CH 2 Cl 2 / Me0H / heptane / NH 3 4: 1: 5: 0.2%) to give 2.0 g of the desired product.

Figure 112003042468427-pct00048
Figure 112003042468427-pct00048

생성물 (1.85 g, 4.00 mmol) 을 EtOH:THF (4: 1) 에 용해한 후, 라니-Ni 및 히드라진 (1.0 mL, 20 mmol) 을 첨가했다. 황색이 없어질 때까지 반응물을 실온에서 3 시간 동안 교반했다. 셀라이트로 여과한 후, 용매를 제거하여, 1.26 g 의 N-(2-아미노-5-(4-tert-부톡시카르보닐-1-피페라지닐)-페닐)벤젠술폰아미드를 수득하여, 추가의 정제없이 사용했다. The product (1.85 g, 4.00 mmol) was dissolved in EtOH: THF (4: 1), followed by Raney-Ni and hydrazine (1.0 mL, 20 mmol). The reaction was stirred at room temperature for 3 hours until yellow disappeared. After filtration through celite, the solvent was removed to yield 1.26 g of N- (2-amino-5- (4-tert-butoxycarbonyl-1-piperazinyl) -phenyl) benzenesulfonamide, Used without further purification.

N-{2-아미노-5-(4-t-부틸옥시카르보닐-피페라지닐)페닐}벤젠술폰아미드 (79 mg, 0.184 mmol) 및 피리딘(131 ㎕, 1.6 mmol) 의 CH2Cl2 (7 mL) 중 용액에, 상이한 술포닐클로라이드 (0.239 mmol) 를 첨가했다. 2 시간 후, 실온에서 용매를 제거했다. 크로마토그래피 (SiO2, CH2Cl2/MeOH/헵탄 4:1:15) 로 정제한 후, 잔사를 소량의 MeOH 에 용해하고 HCl/에테르를 첨가하여 수행되는 Boc-탈보호를 수행했다. 혼합물을 실온에서 0.5 시간 동안 정치시킨 후, 용매를 제거했다. 재결정 (MeOH/에테르) 으로 최종 생성물을 각각 수득했다. CH 2 Cl 2 of N- {2-amino-5- (4-t-butyloxycarbonyl-piperazinyl) phenyl} benzenesulfonamide (79 mg, 0.184 mmol) and pyridine (131 μl, 1.6 mmol) ( To a solution in 7 mL), different sulfonylchloride (0.239 mmol) was added. After 2 hours, the solvent was removed at room temperature. After purification by chromatography (SiO 2 , CH 2 Cl 2 / MeOH / heptane 4: 1: 15), Boc-deprotection was carried out by dissolving the residue in a small amount of MeOH and adding HCl / ether. The mixture was left at room temperature for 0.5 hours before the solvent was removed. Recrystallization (MeOH / ether) gave each final product.

실시예 11 Example 11

N-{4-(1-피페라지닐)-2-[(페닐술포닐)아미노]페닐}-1-나프탈렌술폰아미드 히드로클로라이드 (반응식 2, 방법 4)N- {4- (1-piperazinyl) -2-[(phenylsulfonyl) amino] phenyl} -1-naphthalenesulfonamide hydrochloride (Scheme 2, method 4)

N-{4-(1-피페라지닐)-2-[(페닐술포닐)아미노]페닐}-1-나프탈렌술폰아미드를 N-{2-아미노-5-(4-t-부틸옥시카르보닐-피페라지닐)페닐]벤젠술폰아미드 및 1-나프탈렌술포닐클로라이드 (54 mg, 0.239 mmol) 로부터 일반 방법 3 에 따라 합성해, 40 mg 의 자주색 고체를 수득했다. N- {4- (1-piperazinyl) -2-[(phenylsulfonyl) amino] phenyl} -1-naphthalenesulfonamide to N- {2-amino-5- (4-t-butyloxycarbonyl Synthesis according to General Method 3 from -piperazinyl) phenyl] benzenesulfonamide and 1-naphthalenesulfonylchloride (54 mg, 0.239 mmol) yielded 40 mg of a purple solid.

Figure 112003042468427-pct00049
Figure 112003042468427-pct00049

실시예 12 Example 12

5-(디메틸아미노)-N-{4-(1-피페라지닐)-2-[(페닐술포닐)아미노]페닐}-1-나프탈렌술폰아미드 히드로클로라이드 (반응식 2, 방법 4)5- (dimethylamino) -N- {4- (1-piperazinyl) -2-[(phenylsulfonyl) amino] phenyl} -1-naphthalenesulfonamide hydrochloride (Scheme 2, method 4)

5-(디메틸아미노)-N-{4-(1-피페라지닐)-2-[(페닐술포닐)아미노]페닐}-1-나프탈렌술폰아미드를 N-{2-아미노-5-(4-t-부틸옥시카르보닐피페라지닐)-페닐}벤젠술폰아미드로 및 댄실클로라이드 (64 mg, 0.239 mmol) 로부터 일반 방법 3 에 따라 합성해, 60 mg 의 자주색 고체를 수득했다. 5- (dimethylamino) -N- {4- (1-piperazinyl) -2-[(phenylsulfonyl) amino] phenyl} -1-naphthalenesulfonamide N- {2-amino-5- (4 Synthesized from -t-butyloxycarbonylpiperazinyl) -phenyl} benzenesulfonamide and from dansylchloride (64 mg, 0.239 mmol) according to General Method 3 to give 60 mg of a purple solid.

Figure 112003042468427-pct00050
Figure 112003042468427-pct00050

실시예 13 Example 13                 

N-[2-[(페닐술포닐)아미노]-4-(1-피페라지닐)페닐]-8-퀴놀린술폰아미드 히드로클로라이드 (반응식 2, 방법 4)N- [2-[(phenylsulfonyl) amino] -4- (1-piperazinyl) phenyl] -8-quinolinesulfonamide hydrochloride (Scheme 2, method 4)

N-[2-[(페닐술포닐)아미노]-4-(1-피페라지닐)페닐]-8-퀴놀린술폰아미드를, N-{2-아미노-5-(4-t-부틸옥시카르보닐-피페라지닐)페닐}벤젠술폰아미드 및 8-퀴놀린술포닐클로라이드 (54 mg, 0.239 mmol) 로부터 일반 방법 3 에 따라 합성해, 50 mg 의 자주색 고체를 수득했다. N- [2-[(phenylsulfonyl) amino] -4- (1-piperazinyl) phenyl] -8-quinolinesulfonamide to N- {2-amino-5- (4-t-butyloxycar Synthesis was carried out according to general method 3 from carbonyl-piperazinyl) phenyl} benzenesulfonamide and 8-quinolinesulfonylchloride (54 mg, 0.239 mmol) to give 50 mg of a purple solid.

Figure 112003042468427-pct00051
Figure 112003042468427-pct00051

실시예 14 Example 14

2,4,6-트리메틸-N-[2-[(페닐술포닐)아미노]-4-(1-피페라지닐)페닐]벤젠술폰아미드 히드로클로라이드 (반응식 2, 방법 4) 2,4,6-trimethyl-N- [2-[(phenylsulfonyl) amino] -4- (1-piperazinyl) phenyl] benzenesulfonamide hydrochloride (Scheme 2, method 4)

2,4,6-트리메틸-N-[2-[(페닐술포닐)아미노]-4-(1-피페라지닐)페닐] 벤젠술폰아미드를, N-{2-아미노-5-(4-t-부틸옥시카르보닐피페라지닐)-페닐}벤젠술폰아미드 및 2-메시틸렌술포닐클로라이드 (52 mg, 0.239 mmol) 로부터 일반 방법 3 에 따라 합성하여, 50 mg 의 자주색 고체를 수득했다. 2,4,6-trimethyl-N- [2-[(phenylsulfonyl) amino] -4- (1-piperazinyl) phenyl] benzenesulfonamide, N- {2-amino-5- (4- Synthesis according to General Method 3 from t-butyloxycarbonylpiperazinyl) -phenyl} benzenesulfonamide and 2-mesitylenesulfonylchloride (52 mg, 0.239 mmol) yielded 50 mg of a purple solid.

Figure 112003042468427-pct00052
Figure 112003042468427-pct00052

실시예 15 Example 15

4-메틸-N-[2-[(페닐술포닐)아미노]-4-(1-피페라지닐)페닐]벤젠술폰아미드 히드로클로라이드 (반응식 2, 방법 4) 4-methyl-N- [2-[(phenylsulfonyl) amino] -4- (1-piperazinyl) phenyl] benzenesulfonamide hydrochloride (Scheme 2, method 4)

4-메틸-N-[2-[(페닐술포닐)아미노]-4-(1-피페라지닐)페닐]벤젠술폰아미드를, N-{2-아미노-5-(4-t-부틸옥시카르보닐-피페라지닐)-페닐}벤젠술폰아미드 및 p-톨루엔술포닐클로라이드 (46 mg, 0.239 mmol) 로부터 일반 방법 3 으로부터 합성하여 70 mg 의 자주색 고체를 수득했다. 4-Methyl-N- [2-[(phenylsulfonyl) amino] -4- (1-piperazinyl) phenyl] benzenesulfonamide, N- {2-amino-5- (4-t-butyloxy Carbonyl-piperazinyl) -phenyl} benzenesulfonamide and p-toluenesulfonylchloride (46 mg, 0.239 mmol) were synthesized from General Method 3 to yield 70 mg of purple solid.

Figure 112003042468427-pct00053
Figure 112003042468427-pct00053

실시예 16 Example 16

N-[2-({[(E)-2-페닐에테닐]술포닐}아미노)-5-(1-피페라지닐)페닐]벤젠술폰아미드 히드로클로라이드 (반응식 2, 방법 4)N- [2-({[(E) -2-phenylethenyl] sulfonyl} amino) -5- (1-piperazinyl) phenyl] benzenesulfonamide hydrochloride (Scheme 2, method 4)

N-[2-({[(E)-2-페닐에테닐]술포닐}아미노)-5-(1-피페라지닐)페닐]벤젠술폰아미드를, N-{2-아미노-5-(4-t-부틸옥시카르보닐-피페라지닐)-페닐}벤젠술폰아미드 및 β-스티렌술포닐클로라이드 (48 mg, 0.239 mmol) 로부터 일반 방법 3 에 따라 합성해, Boc-탈보호 전에 160 mg 의 자주색 고체를 수득했다. N- [2-({[(E) -2-phenylethenyl] sulfonyl} amino) -5- (1-piperazinyl) phenyl] benzenesulfonamide, N- {2-amino-5- ( Synthesized according to General Method 3 from 4-t-butyloxycarbonyl-piperazinyl) -phenyl} benzenesulfonamide and β-styrenesulfonylchloride (48 mg, 0.239 mmol), 160 mg of Boc-deprotection before A purple solid was obtained.

Figure 112003042468427-pct00054
Figure 112003042468427-pct00054

실시예 17 Example 17

2,5-디메톡시-N-[2-[(페닐술포닐)아미노]-4-(1-피페라지닐)페닐]벤젠술폰아미드 히드로클로라이드 (반응식 2, 방법 4) 2,5-dimethoxy-N- [2-[(phenylsulfonyl) amino] -4- (1-piperazinyl) phenyl] benzenesulfonamide hydrochloride (Scheme 2, method 4)

2,5-디메톡시-N-[2-[(페닐술포닐)아미노]-4-(1-피페라지닐)페닐]벤젠술폰아 미드를, N-{2-아미노-5-(4-t-부틸옥시카르보닐피페라지닐)-페닐}벤젠술폰아미드 및 2,5-디메톡시벤젠술포닐클로라이드 (57 mg, 0.239 mmol) 로부터 일반 방법 3 으로부터 합성하여 60 mg 의 자주색 고체를 수득했다. 2,5-dimethoxy-N- [2-[(phenylsulfonyl) amino] -4- (1-piperazinyl) phenyl] benzenesulfonamide was substituted with N- {2-amino-5- (4- Synthesis from General Method 3 from t-butyloxycarbonylpiperazinyl) -phenyl} benzenesulfonamide and 2,5-dimethoxybenzenesulfonylchloride (57 mg, 0.239 mmol) yielded 60 mg of a purple solid.

Figure 112003042468427-pct00055
Figure 112003042468427-pct00055

실시예 18 Example 18

2-메틸-N-[2-[(페닐술포닐)아미노]-4-(1-피페라지닐)페닐]벤젠술폰아미드 히드로클로라이드 (반응식 2, 방법 4) 2-methyl-N- [2-[(phenylsulfonyl) amino] -4- (1-piperazinyl) phenyl] benzenesulfonamide hydrochloride (Scheme 2, method 4)

2-메틸-N-[2-[(페닐술포닐)아미노]-4-(1-피페라지닐)페닐]벤젠술폰아미드를, N-{2-아미노-5-(4-t-부톡시카르보닐-피페라지닐)-페닐]벤젠술폰아미드 및 o-톨루엔술포닐클로라이드 (46 mg, 0.239 mmol) 로부터, 일반 방법 3 에 따라 합성하여 Boc-탈보호 전 160 mg 의 자주색 고체를 수득했다. 2-methyl-N- [2-[(phenylsulfonyl) amino] -4- (1-piperazinyl) phenyl] benzenesulfonamide is substituted with N- {2-amino-5- (4-t-butoxy From carbonyl-piperazinyl) -phenyl] benzenesulfonamide and o-toluenesulfonylchloride (46 mg, 0.239 mmol), it was synthesized according to General Method 3 to give 160 mg of purple solid before Boc-deprotection.

Figure 112003042468427-pct00056
Figure 112003042468427-pct00056

실시예 19 Example 19

2,4-디플루오로-N-[2-[(페닐술포닐)아미노]-4-(1-피페라지닐)페닐]벤젠술폰아미드 히드로클로라이드 (반응식 2, 방법 4)2,4-difluoro-N- [2-[(phenylsulfonyl) amino] -4- (1-piperazinyl) phenyl] benzenesulfonamide hydrochloride (Scheme 2, method 4)

2,4-디플루오로-N-[2-[(페닐술포닐)아미노]-4-(1-피페라지닐)페닐] 벤젠술폰아미드를, N-{2-아미노-5-(4-t-부틸옥시카르보닐피페라지닐)-페닐}벤젠술폰아미드 및 2,4-디플루오로벤젠술포닐클로라이드 (94 mg, 0.455 mmol) 로부터 일반 방법 3 에 따라 합성하여, Boc-탈보호 전 160 mg 의 자주색 고체를 수득했다. 2,4-difluoro-N- [2-[(phenylsulfonyl) amino] -4- (1-piperazinyl) phenyl] benzenesulfonamide, N- {2-amino-5- (4- t-Butyloxycarbonylpiperazinyl) -phenyl} benzenesulfonamide and 2,4-difluorobenzenesulfonylchloride (94 mg, 0.455 mmol) synthesized according to General Method 3, before Boc-deprotection 160 mg of a purple solid were obtained.

Figure 112003042468427-pct00057
Figure 112003042468427-pct00057

실시예 20 Example 20

4-부톡시-N-[2-[(페닐술포닐)아미노]-4-(1-피페라지닐)페닐]벤젠술폰아미드 히드로클로라이드 (반응식 2, 방법 4)4-butoxy-N- [2-[(phenylsulfonyl) amino] -4- (1-piperazinyl) phenyl] benzenesulfonamide hydrochloride (Scheme 2, method 4)

4-부톡시-N-[2-[(페닐술포닐)아미노]-4-(1-피페라지닐)페닐]벤젠술폰아미드를, N-{2-아미노-5-(4-t부틸옥시카르보닐-피페라지닐)-페닐}벤젠술폰아미드 및 4-n부톡시벤젠술포닐클로라이드 (59 mg, 0.239 mmol) 로부터 일반 방법 3 에 따라 합성하여 70 mg 의 자주색 고체를 수득했다. 4-butoxy-N- [2-[(phenylsulfonyl) amino] -4- (1-piperazinyl) phenyl] benzenesulfonamide, N- {2-amino-5- (4-tbutyloxy Synthesis according to General Method 3 from carbonyl-piperazinyl) -phenyl} benzenesulfonamide and 4-nbutoxybenzenesulfonylchloride (59 mg, 0.239 mmol) yielded 70 mg of a purple solid.

Figure 112003042468427-pct00058
Figure 112003042468427-pct00058

실시예 21 Example 21

3,5-디메틸-N-[2-[(페닐술포닐)아미노]-4-(1-피페라지닐)페닐]-4-이속사졸술폰아미드 히드로클로라이드 (반응식 2, 방법 4)3,5-dimethyl-N- [2-[(phenylsulfonyl) amino] -4- (1-piperazinyl) phenyl] -4-isoxazolesulfonamide hydrochloride (Scheme 2, method 4)

3,5-디메틸-N-[2-[(페닐술포닐)아미노]-4-(1-피페라지닐)페닐]-4-이속사졸술폰아미드를, N-{2-아미노-5-(4-t-부틸옥시카르보닐피페라지닐)-페닐}벤젠술폰아미드 및 3,5-디메틸이속사졸술포닐클로라이드 (47 mg, 0.239 mmol) 로부터 일반 방법 3 으로 합성하여, 70 mg 의 자주색 고체를 수득했다. 3,5-dimethyl-N- [2-[(phenylsulfonyl) amino] -4- (1-piperazinyl) phenyl] -4-isoxazolsulfonamide is substituted with N- {2-amino-5- ( 70 mg of a purple solid, synthesized by the general method 3 from 4-t-butyloxycarbonylpiperazinyl) -phenyl} benzenesulfonamide and 3,5-dimethylisoxazolesulfonylchloride (47 mg, 0.239 mmol) Obtained.

Figure 112003042468427-pct00059
Figure 112003042468427-pct00059

실시예 22 Example 22

5-플루오로-2-메틸-N-[2-[(페닐술포닐)아미노]-4-(1-피페라지닐)페닐]벤젠술폰아미드 (반응식 2, 방법 4)5-fluoro-2-methyl-N- [2-[(phenylsulfonyl) amino] -4- (1-piperazinyl) phenyl] benzenesulfonamide (Scheme 2, method 4)

5-플루오로-2-메틸-N-[2-[(페닐술포닐)아미노]-4-(1-피페라지닐)페닐]벤젠술폰아미드를, N-{2-아미노-5-(4-t-부틸옥시카르보닐피페라지닐)-페닐}벤젠술폰아미드 및 5-플루오로-2-메틸벤젠술포닐클로라이드 (50 mg, 0.239 mmol) 로부터, 일반 방법 3 에 따라 합성해, 60 mg 의 자주색 고체를 수득했다. 5-Fluoro-2-methyl-N- [2-[(phenylsulfonyl) amino] -4- (1-piperazinyl) phenyl] benzenesulfonamide, N- {2-amino-5- (4 From -t-butyloxycarbonylpiperazinyl) -phenyl} benzenesulfonamide and 5-fluoro-2-methylbenzenesulfonylchloride (50 mg, 0.239 mmol), synthesized according to General Method 3, to 60 mg of A purple solid was obtained.

Figure 112003042468427-pct00060
Figure 112003042468427-pct00060

실시예 23 Example 23

4-(메틸술포닐)-N-[2-[(페닐술포닐)아미노]-4-(1-피페라지닐)페닐]벤젠술폰아미드 히드로클로라이드 (반응식 2, 방법 4)4- (methylsulfonyl) -N- [2-[(phenylsulfonyl) amino] -4- (1-piperazinyl) phenyl] benzenesulfonamide hydrochloride (Scheme 2, method 4)

4-(메틸술포닐)-N-[2-[페닐술포닐)아미노]-4-(1-피페라지닐)페닐]벤젠술폰아미드를, N-{2-아미노-5-(4-t-부틸옥시카르보닐피페라지닐)-페닐}벤젠술폰아미드 및 4-메틸술포닐벤젠술포닐클로라이드 (61 mg, 0.455 mmol) 로부터 일반 방법 3 에 따라 합성해 70 mg 의 자주색 고체를 수득했다. 4- (methylsulfonyl) -N- [2- [phenylsulfonyl) amino] -4- (1-piperazinyl) phenyl] benzenesulfonamide is substituted with N- {2-amino-5- (4-t -Butyloxycarbonylpiperazinyl) -phenyl} benzenesulfonamide and 4-methylsulfonylbenzenesulfonylchloride (61 mg, 0.455 mmol) were synthesized according to the general method 3 to give 70 mg of purple solid.

Figure 112003042468427-pct00061
Figure 112003042468427-pct00061

실시예 24 Example 24

2-(메틸술포닐)-N-[2-[(페닐술포닐)아미노]-4-(1-피페라지닐)페닐]벤젠술폰아미드 히드로클로라이드 (반응식 2, 방법 4)2- (methylsulfonyl) -N- [2-[(phenylsulfonyl) amino] -4- (1-piperazinyl) phenyl] benzenesulfonamide hydrochloride (Scheme 2, method 4)

2-(메틸술포닐)-N-[2-[(페닐술포닐)아미노]-4-(1-피페라지닐)페닐]벤젠술폰아미드를, N-{2-아미노-5-(4-t부틸옥시카르보닐-피페라지닐)-페닐}벤젠술폰아미드 및 2-메틸술포닐벤젠술포닐클로라이드 (61 mg, 0.239 mmol) 로부터 일반 방법 3 에 따라 합성하여 70 mg 의 자주색 고체를 수득했다. 2- (methylsulfonyl) -N- [2-[(phenylsulfonyl) amino] -4- (1-piperazinyl) phenyl] benzenesulfonamide is substituted with N- {2-amino-5- (4- Synthesis according to General Method 3 from tbutyloxycarbonyl-piperazinyl) -phenyl} benzenesulfonamide and 2-methylsulfonylbenzenesulfonylchloride (61 mg, 0.239 mmol) yielded 70 mg of a purple solid.

Figure 112003042468427-pct00062
Figure 112003042468427-pct00062

실시예 25 Example 25

2-메톡시-4-메틸-N-[2-[(페닐술포닐)아미노]-4-(1-피페라진)페닐]벤젠술폰아미드 히드로클로라이드 (반응식 2, 방법 4)2-methoxy-4-methyl-N- [2-[(phenylsulfonyl) amino] -4- (1-piperazin) phenyl] benzenesulfonamide hydrochloride (Scheme 2, method 4)

2-메톡시-4-메틸-N-[2-[(페닐술포닐)아미노]-4-(1-피페라지닐)페닐]벤젠술폰아미드를, N-{2-아미노-5-(4-t-부톡시카르보닐피페라지닐)-페닐}벤젠술폰아미드 및 2-메톡시-4-메틸벤젠술포닐클로라이드 (53 mg, 0.239 mmol) 로부터 일반 방법 3 에 따라 합성해, 8O mg 의 자주색 고체를 수득했다. 2-methoxy-4-methyl-N- [2-[(phenylsulfonyl) amino] -4- (1-piperazinyl) phenyl] benzenesulfonamide, N- {2-amino-5- (4 80 mg of purple, synthesized according to General Method 3 from -t-butoxycarbonylpiperazinyl) -phenyl} benzenesulfonamide and 2-methoxy-4-methylbenzenesulfonylchloride (53 mg, 0.239 mmol) A solid was obtained.

Figure 112003042468427-pct00063
Figure 112003042468427-pct00063

실시예 26 Example 26

4-메톡시-2-메틸-N-[2-[(페닐술포닐)아미노]-4-(1-피페라지닐)페닐]벤젠술폰 아미드 히드로클로라이드 (반응식 2, 방법 4) 4-methoxy-2-methyl-N- [2-[(phenylsulfonyl) amino] -4- (1-piperazinyl) phenyl] benzenesulfon amide hydrochloride (Scheme 2, method 4)

4-메톡시-2-메틸-N-[2-[(페닐술포닐)아미노]-4-(1-피페라지닐)페닐]벤젠술폰아미드를, N-{2-아미노-5-(4-t-부틸옥시카르보닐피페라지닐)-페닐}벤젠술폰아미드 및 2-메틸-4-트리플루오로메톡시벤젠술포닐클로라이드 (53 mg, 0.455 mmol) 로부터 일반 방법 3 에 따라 합성해 Boc-탈보호 전에 70 mg 의 자주색 고체를 수득했다.4-methoxy-2-methyl-N- [2-[(phenylsulfonyl) amino] -4- (1-piperazinyl) phenyl] benzenesulfonamide, N- {2-amino-5- (4 -t-Butyloxycarbonylpiperazinyl) -phenyl} benzenesulfonamide and 2-methyl-4-trifluoromethoxybenzenesulfonylchloride (53 mg, 0.455 mmol) synthesized according to the general method 3 according to Boc-de 70 mg of a purple solid were obtained before protection.

Figure 112003042468427-pct00064
Figure 112003042468427-pct00064

실시예 27 Example 27

N-{4-(호모피페라지닐)-2-[(페닐술포닐)아미노]페닐}벤젠술폰아미드 히드로클로라이드 (반응식 1, 방법 2)N- {4- (homopiperazinyl) -2-[(phenylsulfonyl) amino] phenyl} benzenesulfonamide hydrochloride (Scheme 1, method 2)

벤젠술포닐 클로라이드 (0.088 g, 0.50 mmol) 를, 2-아미노-5-(4-t-부틸옥시카르보닐-호모피페라진-1-일)아닐린 (0.153 g, 0.50 mmol) 및 피리딘 (514 mL, 6.3 9 mmol) 의 DCM 중 용액에 첨가했다. 실온에서 1 시간 후, 혼합물을 NaHCO3 (10 %) 로 세척하고, 건조 (MgSO4) 하고 용매를 제거했다. 칼럼 크로마토그래피 (CH2Cl2/MeOH/헵탄 4:1:15) 로 정제하여 N-{2-아미노-4-[4-t-부틸옥시카르보닐호모피페라진-1-일-]페닐}벤젠술폰아미드 및 비스-술포닐화 N-{4-[4-t부틸옥시카르보닐]호모피페라지닐)-2-[(페닐술포닐)아미노]페닐)벤젠술폰아미드 (0.150 g, 86 %) 의 혼합물을 수득했다. 혼합물을 MeOH 에 용해시키고 HCl/에테르를 첨가하여 Boc-탈보호를 수행했다. 혼합물을 실온에 0.5 시간 정치했다. 예비 HPLC 에 의 한 정제로 N-{4-(호모피페라지닐)-2-[(페닐술포닐)아미노]페닐]벤젠술폰아미드 히드로클로라이드를 수득했다; 분석치 (C23H27ClN4O4S2) C, H, N, S; M+ 487.4 계산치 486.14. 및 N-{4-(호모피페라지닐)-2-[(페닐술포닐)아미노]페닐}벤젠술폰아미드 히드로클로라이드; 분석치 (C17H23ClN402S) C, H, N, S; M+ 347.5 계산치 346.15. Benzenesulfonyl chloride (0.088 g, 0.50 mmol) was dissolved in 2-amino-5- (4-t-butyloxycarbonyl-homopiperazin-1-yl) aniline (0.153 g, 0.50 mmol) and pyridine (514 mL 6.3 9 mmol) was added to the solution in DCM. After 1 h at rt, the mixture was washed with NaHCO 3 (10%), dried (MgSO 4 ) and the solvent removed. Purified by column chromatography (CH 2 Cl 2 / MeOH / heptane 4: 1: 15) to give N- {2-amino-4- [4-t-butyloxycarbonylhompiperazin-1-yl-] phenyl} Benzenesulfonamide and bis-sulfonylated N- {4- [4-tbutyloxycarbonyl] homopiperazinyl) -2-[(phenylsulfonyl) amino] phenyl) benzenesulfonamide (0.150 g, 86%) A mixture of was obtained. The mixture was dissolved in MeOH and HCl / ether was added to perform Boc-deprotection. The mixture was allowed to stand at room temperature for 0.5 hour. Purification by preparative HPLC gave N- {4- (homopiperazinyl) -2-[(phenylsulfonyl) amino] phenyl] benzenesulfonamide hydrochloride; Anal (C 23 H 27 ClN 4 O 4 S 2 ) C, H, N, S; M + 487.4 calculated 486.14. And N- {4- (homopiperazinyl) -2-[(phenylsulfonyl) amino] phenyl} benzenesulfonamide hydrochloride; Anal (C 17 H 23 ClN 4 0 2 S) C, H, N, S; M + 347.5 calcd 346.15.

실시예 28 Example 28

N-(4-(1,4-디아제판-1-일)-2-{[(3-플루오로페닐)술포닐]아미노}페닐)-3-플루오로벤젠술폰아미드 히드로클로라이드 (반응식 1, 방법 2)N- (4- (1,4-diazepane-1-yl) -2-{[(3-fluorophenyl) sulfonyl] amino} phenyl) -3-fluorobenzenesulfonamide hydrochloride (Scheme 1, Method 2)

화합물을 2-아미노-5-(4-t-부틸옥시카르보닐-1-호모피페라지닐)아닐린 및 3-플루오로벤젠술포닐 클로라이드로부터 제조했다. 칼럼 크로마토그래피 (CH2Cl2/Me0H/헵탄, 4:1:15) 에 의한 정제로 N-{2-아미노-5-[4-t부틸옥시카르보닐-호모피페라진-1-일]페닐}-3-플루오로벤젠술폰아미드 및 N-{4-[4-t부틸옥시카르보닐]호모피페라지닐)-2-[(3-플루오로페닐술포닐)아미노]페닐}-3-플루오로벤젠술폰아미드 (O.18O g, 73%) 의 혼합물을 수득했다. 혼합물을 소량의 MeOH 에 용해하고, HCl/에테르를 첨가하여 Boc-탈보호를 수행했다. 혼합물을 실온에서 0.5 시간 동안 정치했다. 예비 HPLC 에 의한 정제로 N-(4-(1,4-디아제판-1-일)-2-{[(3-플루오로페닐)술포닐]아미노}페닐)-3-플루오로벤젠술폰아미드 히드로클로라이드를 수득했다. 분석치 (C23H27ClN404S2) C, H, N, S; M + 524.4 계산치 522.12. The compound was prepared from 2-amino-5- (4-t-butyloxycarbonyl-1-homopiperazinyl) aniline and 3-fluorobenzenesulfonyl chloride. Purification by column chromatography (CH 2 Cl 2 / Me0H / heptane, 4: 1: 15) gave N- {2-amino-5- [4-tbutyloxycarbonyl-homopiperazin-1-yl] phenyl } -3-fluorobenzenesulfonamide and N- {4- [4-tbutyloxycarbonyl] homopiperazinyl) -2-[(3-fluorophenylsulfonyl) amino] phenyl} -3-fluoro A mixture of robenzenesulfonamide (O.18O g, 73%) was obtained. The mixture was dissolved in a small amount of MeOH and Boc-deprotection was performed by addition of HCl / ether. The mixture was allowed to stand at rt for 0.5 h. Purification by preparative HPLC gave N- (4- (1,4-diazepane-1-yl) -2-{[(3-fluorophenyl) sulfonyl] amino} phenyl) -3-fluorobenzenesulfonamide Hydrochloride was obtained. Anal (C 23 H 27 ClN 4 0 4 S 2 ) C, H, N, S; M + 524.4 calc. 522.12.

실시예 29 Example 29

N-{4-(1,4-디아제판-1-일)-2-[에틸(페닐술포닐)아미노]페닐}벤젠술폰아미드 히드로클로라이드 (반응식 1, 방법 2)N- {4- (1,4-diazepane-1-yl) -2- [ethyl (phenylsulfonyl) amino] phenyl} benzenesulfonamide hydrochloride (Scheme 1, method 2)

벤젠술포닐 클로라이드 (0.579 mL, 4.53 mmol) 의 DCM (2.0 mL) 중 용액에, tert-부틸 4-[4-아미노-3-(에틸아미노)페닐]-1,4-디아제판-1-카르복실레이트 (0.605 g, 1.81 mmol) 및 피리딘 (1.02 mL, 12.67 mmol) 의 DCM (8.0 mL) 중 용액을 첨가했다. 혼합물을 실온에서 16 시간 동안 교반한 후 농축했다. 미정제 성분을 CHCl3/10% MeOH + 0.4% NH3 를 사용하는 실리카 상의 칼럼 크로마토그래피로 정제했다. HCl-에테르/EtOAc 를 이용한 탈보호로 0.365 g 의 미정제 생성물을 HCl-염으로 수득했다. 역상 예비 HPLC 상의 정제로 94 mg 의 생성물을 아세트산 염으로 수득하여, HCl 염으로 전환하고, MeOH/에테르로부터 재결정했다: 수율 64 mg. To a solution of benzenesulfonyl chloride (0.579 mL, 4.53 mmol) in DCM (2.0 mL), tert-butyl 4- [4-amino-3- (ethylamino) phenyl] -1,4-diazepane-1-cart A solution of carboxylate (0.605 g, 1.81 mmol) and pyridine (1.02 mL, 12.67 mmol) in DCM (8.0 mL) was added. The mixture was stirred at rt for 16 h and then concentrated. The crude component was purified by column chromatography on silica using CHCl 3 /10% MeOH + 0.4% NH 3 . Deprotection with HCl-ether / EtOAc gave 0.365 g of crude product as HCl-salt. Purification on reverse phase preparative HPLC gave 94 mg of product as acetic acid salt, converted to HCl salt and recrystallized from MeOH / ether: yield 64 mg.

Figure 112003042468427-pct00065
Figure 112003042468427-pct00065

방법 4 (반응식 2) Method 4 (Scheme 2)

각종 술포닐클로라이드를, N-{2-아미노-5-(4-t-부틸옥시카르보닐-1,4-디아제판-1-일)-페닐}벤젠술폰아미드 및 피리딘 (135 ㎕, 1.7 mmol) 의 DCM (7mL) 중 용액에 첨가했다. 실온에서 1 시간 후, 용매를 제거했다. 칼럼 크로마토그래피 (CH2Cl2/MeOH/헵탄, 4:1:15) 에 의한 정제, 및 잔사를 소량의 MeOH 에 용해하고 HCl/에테르를 첨가하여 수행하는 Boc-탈보호를 수행했다. 혼합물을 실온에서 0.5 시간 동안 정치시킨 후, 용매를 제거했다. 재결정 (MeOH/에테르) 으로 최종 생성물을 수득했다. Various sulfonyl chlorides were prepared using N- {2-amino-5- (4-t-butyloxycarbonyl-1,4-diazepan-1-yl) -phenyl} benzenesulfonamide and pyridine (135 μl, 1.7 mmol ) In a solution in DCM (7 mL). After 1 hour at room temperature, the solvent was removed. Purification by column chromatography (CH 2 Cl 2 / MeOH / heptane, 4: 1: 15) and Boc-deprotection performed by dissolving the residue in a small amount of MeOH and adding HCl / ether. The mixture was left at room temperature for 0.5 hours before the solvent was removed. Recrystallization (MeOH / ether) gave the final product.

실시예 30 Example 30

N-{5-(1,4-디아제판-1-일)-2-[(메틸술포닐)아미노]페닐}벤젠술폰아미드 (반응식 2, 방법 4) N- {5- (1,4-diazepane-1-yl) -2-[(methylsulfonyl) amino] phenyl} benzenesulfonamide (Scheme 2, method 4)

N-{5-(1,4-디아제판-1-일)-2-[(메틸술포닐)아미노]페닐}벤젠술폰아미드를, N-{2-아미노-5-(4-t-부틸옥시카르보닐-1,4-디아제판-1-일)페닐}벤젠술폰아미드 (0.075 g, 0.16 mmol) 및 메탄술포닐 클로라이드 (0.017 mL, 0.22 mmol) 로부터 합성하여, 41.6 mg 의 밝은 자주색 고체를 수득했다; N- {5- (1,4-diazepane-1-yl) -2-[(methylsulfonyl) amino] phenyl} benzenesulfonamide; N- {2-amino-5- (4-t-butyl Synthesized from oxycarbonyl-1,4-diazepane-1-yl) phenyl} benzenesulfonamide (0.075 g, 0.16 mmol) and methanesulfonyl chloride (0.017 mL, 0.22 mmol) to give 41.6 mg of a light purple solid. Obtained;

Figure 112003042468427-pct00066
Figure 112003042468427-pct00066

실시예 31 Example 31

N-{5-(1,4-디아제판-1-일)-2-[(에틸술포닐)아미노]페닐}벤젠술폰아미드 히드로클로라이드 (반응식 2, 방법 4)N- {5- (1,4-diazepane-1-yl) -2-[(ethylsulfonyl) amino] phenyl} benzenesulfonamide hydrochloride (Scheme 2, method 4)

N-{5-(1,4-디아제판-1-일)-2-[(에틸술포닐)아미노]페닐}벤젠술폰아미드 히드로클로라이드를, N-{2-아미노-5-(4-t-부틸옥시카르보닐-1,4-디아제판-1-일)-페닐}벤젠술폰아미드 (0.085 g, 0.19 mmol) 및 에탄술포닐 클로라이드 (0.032 ㎕, 0.25 mmol) 로부터 합성하여, 29.1 mg 의 밝은 자주색 고체를 수득했다; N- {5- (1,4-diazepane-1-yl) -2-[(ethylsulfonyl) amino] phenyl} benzenesulfonamide hydrochloride, N- {2-amino-5- (4-t 29.1 mg of bright, synthesized from -butyloxycarbonyl-1,4-diazepane-1-yl) -phenyl} benzenesulfonamide (0.085 g, 0.19 mmol) and ethanesulfonyl chloride (0.032 μL, 0.25 mmol) A purple solid was obtained;

Figure 112003042468427-pct00067
Figure 112003042468427-pct00067

실시예 32 Example 32

N-{4-(1,4-디아제판-1-일)-2-[(페닐술포닐)아미노]페닐}[1,1'-비페닐]-4-술 폰아미드 히드로클로라이드 (반응식 2, 방법 4)N- {4- (1,4-diazepane-1-yl) -2-[(phenylsulfonyl) amino] phenyl} [1,1'-biphenyl] -4-sulfonamide hydrochloride (Scheme 2 , Method 4)

N-{4-(1,4-디아제판-1-일)-2-[(페닐술포닐)아미노]페닐}[1,1'-비페닐]-4-술폰아미드 히드로클로라이드를, N-{2-아미노-5-(4-t-부틸옥시카르보닐-1,4-디아제판 -1-일)-페닐}벤젠술폰아미드 (0.081 g, 0.18 mmol) 및 1,1'-비페닐-4-술포닐 클로라이드 (0.059 g, 0.24 mmol) 로부터 합성하여, 42.9 mg 의 밝은 자주색 고체를 수득했다; 분석치 (C24H27ClN403S) C, H, N, S; M+ 563.5 계산치 563.17. N- {4- (1,4-diazepane-1-yl) -2-[(phenylsulfonyl) amino] phenyl} [1,1'-biphenyl] -4-sulfonamide hydrochloride, N- {2-Amino-5- (4-t-butyloxycarbonyl-1,4-diazepane-1-yl) -phenyl} benzenesulfonamide (0.081 g, 0.18 mmol) and 1,1'-biphenyl- Synthesis from 4-sulfonyl chloride (0.059 g, 0.24 mmol) gave 42.9 mg of a light purple solid; Anal (C 24 H 27 ClN 4 0 3 S) C, H, N, S; M + 563.5 calcd 563.17.

실시예 33 Example 33

N-(2,1,3-벤족사디아졸-4-일)-4-(1,4-디아제판-1-일)-2-[(페닐술포닐)아미노]벤젠술폰아미드 히드로클로라이드 (반응식 2, 방법 4)N- (2,1,3-benzoxadiazol-4-yl) -4- (1,4-diazepane-1-yl) -2-[(phenylsulfonyl) amino] benzenesulfonamide hydrochloride ( Scheme 2, method 4)

N-(2,1,3-벤족사디아졸-4-일)-4-(1,4-디아제판-1-일)-2-[(페닐술포닐)아미노]벤젠술폰아미드 히드로클로라이드를, N-{2-아미노-5-(4-t-부틸옥시카르보닐- 1,4-디아제판-1-일)-페닐}벤젠술폰아미드 (0.072 g, 0.16 mmol) 및 2,1,3-벤족사디아졸-4-일 술포닐 클로라이드 (0.072 g, 0.21 mmol) 로부터 합성하여, 38.0 mg 의 밝은 자주색 고체를 수득했다. N- (2,1,3-benzoxadiazol-4-yl) -4- (1,4-diazepane-1-yl) -2-[(phenylsulfonyl) amino] benzenesulfonamide hydrochloride , N- {2-amino-5- (4-t-butyloxycarbonyl-1,4-diazepane-1-yl) -phenyl} benzenesulfonamide (0.072 g, 0.16 mmol) and 2,1,3 Synthesis from benzoxadiazol-4-yl sulfonyl chloride (0.072 g, 0.21 mmol) gave 38.0 mg of a light purple solid.

Figure 112003042468427-pct00068
Figure 112003042468427-pct00068

실시예 34 Example 34

N-{4-(1,4-디아제판-1-일)-2-[(페닐술포닐)아미노]페닐}-2-나프탈렌술폰아미드 히드로클로라이드 (반응식 2, 방법 4)N- {4- (1,4-diazepane-1-yl) -2-[(phenylsulfonyl) amino] phenyl} -2-naphthalenesulfonamide hydrochloride (Scheme 2, method 4)

N-{4-(1,4-디아제판-1-일)-2-[(페닐술포닐)아미노]페닐]-2-나프탈렌술폰아미드 히드로클로라이드를, N-{2-아미노-5-(4-t부틸옥시카르보닐- 1,4-디아제판-1-일)-페닐}벤젠술폰아미드 (0.084 g, 0.19 mmol) 및 2-나프틸술포닐 클로라이드 (0.055 mL, 0.24 mmol) 로부터 합성하여, 67.8 mg 의 밝은 자주색 고체를 수득했다; 분석치 (C24H27ClN403S) C, H, N, S; M+ 529.2 계산치 529.12. N- {4- (1,4-diazepane-1-yl) -2-[(phenylsulfonyl) amino] phenyl] -2-naphthalenesulfonamide hydrochloride, N- {2-amino-5- ( Synthesized from 4-tbutyloxycarbonyl-1,4-diazepane-1-yl) -phenyl} benzenesulfonamide (0.084 g, 0.19 mmol) and 2-naphthylsulfonyl chloride (0.055 mL, 0.24 mmol), 67.8 mg of a light purple solid were obtained; Anal (C 24 H 27 ClN 4 0 3 S) C, H, N, S; M + 529.2 calcd 529.12.

실시예 35 Example 35

N-{4-(1,4-디아제판-1-일)-2-[(메틸술포닐)아미노]페닐}벤젠술폰아미드 히드로클로라이드 (반응식 2, 방법 4)N- {4- (1,4-diazepane-1-yl) -2-[(methylsulfonyl) amino] phenyl} benzenesulfonamide hydrochloride (Scheme 2, method 4)

벤젠술포닐클로라이드 (0.233 g, 1.8 mmol) 를 N-{5-(4-t부틸옥시카르보닐-1,4-디아제판-1-일)-2-아미노]페닐}메탄술폰아미드 (0.540 g, 1.4 mmol) 및 피리딘 (0.995 mL, 12.6 mmol) 의 DCM (40 mL) 중 용액에 첨가했다. 실온에서 2 시간 후, 용매를 제거했다. 칼럼 크로마토그래피 (DCM/MeOH/헵탄 4:1:5) 에 의한 정제로, 580 mg (79 %) 의 밝은 자주색 고체를 수득했다. Boc-탈보호는, 화합물을 소량의 MeOH 에 용해시키고 HCl/에테르를 첨가하여 수행했다. 용매를 제거하고, 생성물을 MeOH/에테르로부터 재결정했다. M+1 425.2 계산치 425.12 Benzenesulfonylchloride (0.233 g, 1.8 mmol) to N- {5- (4-tbutyloxycarbonyl-1,4-diazepane-1-yl) -2-amino] phenyl} methanesulfonamide (0.540 g , 1.4 mmol) and pyridine (0.995 mL, 12.6 mmol) were added to a solution in DCM (40 mL). After 2 hours at room temperature, the solvent was removed. Purification by column chromatography (DCM / MeOH / heptane 4: 1: 5) gave 580 mg (79%) of a light purple solid. Boc-deprotection was performed by dissolving the compound in a small amount of MeOH and adding HCl / ether. Solvent was removed and the product was recrystallized from MeOH / ether. M + 1 425.2 calc.425.12

실시예 36 Example 36

N-{4-(1,4-디아제판-1-일)-2-[메틸(메틸술포닐)아미노]페닐}벤젠술폰아미드히드로클로라이드 (반응식 2, 방법 4)N- {4- (1,4-diazepane-1-yl) -2- [methyl (methylsulfonyl) amino] phenyl} benzenesulfonamidehydrochloride (Scheme 2, method 4)

MeI (45 ㎕, 0.72 mmol) 를 N-{4-(4-t-부틸옥시카르보닐-1,4-디아제판-1-일) [(메틸술포닐)아미노]페닐}벤젠술폰아미드 (0.189 g, 0.36 mmol) 및 K2CO3 (0.124, 0.90 mmol) 의 아세톤 (25 mL) 중 용액에 첨가했다. 혼합물을 실온에서 2 시간 동안 교반하고 여과하고 용매를 제거했다. 칼럼 크로마토그래피 (DCM/MeOH/헵탄 4:1:15) 로 110 mg 의 N-{4-(4-t-부틸옥시카르보닐-1,4-디아제판-1-일)-2-[메틸(메틸술포닐)아미노]-페닐}벤젠술폰아미드 및 20 mg 의 N-{4-(4-t-부틸옥시카르보닐 1,4-디아제판-1-일)-2-[(메틸술포닐)아미노]페닐}-N-메틸벤젠술폰아미드를 수득했다. Boc-탈보호는, 화합물을 소량의 MeOH 에 용해하고, HCl/에테르를 첨가하여 수행했다. 용매를 제거하고 생성물을 MeOH/에테르로부터 재결정했다. N-{4-(1,4-디아제판-1-일)-2-[메틸(메틸술포닐)아미노]페닐)벤젠술폰아미드 히드로클로라이드 M+1 439.2 계산치 439.14 MeI (45 μl, 0.72 mmol) was diluted with N- {4- (4-t-butyloxycarbonyl-1,4-diazepane-1-yl) [(methylsulfonyl) amino] phenyl} benzenesulfonamide (0.189 g, 0.36 mmol) and K 2 CO 3 (0.124, 0.90 mmol) were added to a solution in acetone (25 mL). The mixture was stirred at rt for 2 h, filtered and the solvent removed. 110 mg of N- {4- (4-t-butyloxycarbonyl-1,4-diazepan-1-yl) -2- [methyl by column chromatography (DCM / MeOH / heptane 4: 1: 15) (Methylsulfonyl) amino] -phenyl} benzenesulfonamide and 20 mg of N- {4- (4-t-butyloxycarbonyl 1,4-diazepane-1-yl) -2-[(methylsulfonyl ) Amino] phenyl} -N-methylbenzenesulfonamide was obtained. Boc-deprotection was performed by dissolving the compound in a small amount of MeOH and adding HCl / ether. Solvent was removed and the product was recrystallized from MeOH / ether. N- {4- (1,4-diazepane-1-yl) -2- [methyl (methylsulfonyl) amino] phenyl) benzenesulfonamide hydrochloride M + 1 439.2 calc. 439.14

실시예 37Example 37

N-{4-(1,4-디아제판-1-일)-2-[(메틸술포닐)아미노]페닐}-N-메틸벤젠술폰아미드 히드로클로라이드 (반응식 2, 방법 4)N- {4- (1,4-diazepane-1-yl) -2-[(methylsulfonyl) amino] phenyl} -N-methylbenzenesulfonamide hydrochloride (Scheme 2, method 4)

MeI (45 ㎕, 0.72 mmol) 를 N-{4-(4-t-부틸옥시카르보닐-1,4-디아제판-1-일) -2-[(메틸술포닐)아미노]페닐]벤젠술폰아미드 (0.189 g, 0.36 mmol) 및 K2CO3 (0.124 g, 0.90 mmol) 의 아세톤 (25 mL) 중 혼합물에 첨가했다. 혼합물을 실온에서 2 시간동안 교반하고 여과하여, 용매를 제거했다. 칼럼 크로마토그래피 (DCM/MeOH/헵탄 4:1:15) 에 의한 정제로 110 mg 의 N-{4-(4-t-부틸옥시카르보닐 1,4-디아제판-1-일)-2-[메틸(메틸술포닐)아미노]페닐]벤젠술폰아미드 및 20 mg 의 N-{4-(4-t부틸옥시카르보닐-1,4-디아제판-1-일)-2-[(메틸술포닐)아미노]페닐]-N-메틸벤젠술폰아미드를 수득했다. Boc-탈보호는, 화합물을 소량의 MeOH 에 용해하고, HCl/에테르를 첨가하여 수행했다. 용매를 제거하고, 생성물을 MeOH/에테르로부터 재결정했다. N-{4-(1,4-디아제판-1-일)-2-[(메틸술포닐)아미노]페닐}-N-메틸벤젠술폰아미드 히드로클로라이드 M+1 439.2 계산치 439.14 MeI (45 μl, 0.72 mmol) was diluted with N- {4- (4-t-butyloxycarbonyl-1,4-diazepane-1-yl) -2-[(methylsulfonyl) amino] phenyl] benzenesulphone To a mixture of amide (0.189 g, 0.36 mmol) and K 2 CO 3 (0.124 g, 0.90 mmol) in acetone (25 mL). The mixture was stirred at rt for 2 h and filtered to remove the solvent. Purification by column chromatography (DCM / MeOH / heptane 4: 1: 15) gave 110 mg of N- {4- (4-t-butyloxycarbonyl 1,4-diazepane-1-yl) -2- [Methyl (methylsulfonyl) amino] phenyl] benzenesulfonamide and 20 mg of N- {4- (4-tbutyloxycarbonyl-1,4-diazepan-1-yl) -2-[(methylsul Ponyl) amino] phenyl] -N-methylbenzenesulfonamide was obtained. Boc-deprotection was performed by dissolving the compound in a small amount of MeOH and adding HCl / ether. Solvent was removed and the product was recrystallized from MeOH / ether. N- {4- (1,4-diazepane-1-yl) -2-[(methylsulfonyl) amino] phenyl} -N-methylbenzenesulfonamide hydrochloride M + 1 439.2 calc. 439.14

실시예 38 Example 38

N-{4-(1,4-디아제판-1-일)-2-[메틸(페닐술포닐)아미노]페닐}벤젠술폰아미드 히드로클로라이드 (반응식 2, 방법 4)N- {4- (1,4-diazepane-1-yl) -2- [methyl (phenylsulfonyl) amino] phenyl} benzenesulfonamide hydrochloride (Scheme 2, method 4)

MeI (45 ㎕, 0.72 mmol) 를 N-{4-(4-t-부틸옥시카르보닐-1,4-디아제판-1-일)-2-[(페닐술포닐)아미노]페닐}벤젠술폰아미드 (0.189 g, 0.36 mmol) 및 K2CO3 (0.124, 0.90 mmol) 의 아세톤 (25 mL) 중 혼합물에 첨가했다. 혼합물을 실온에서 2 시간 동안 교반하고, 여과하여 용매를 제거했다. 칼럼 크로마토그래피 (DCM/MeOH/헵탄 4:1:15) 에 의한 정제로 N-{4-(4-t-부틸옥시카르보닐-1,4-디아제판-1-일)-2-[메틸(페닐술포닐)-아미노]페닐}벤젠술폰아미드를 무색 오일로서 수득했다. Boc-탈보호는, 화합물을 소량의 MeOH 에 용해하고 HCl/에테르를 첨가하여 수행했다. 용매를 제거하고, 잔사를 MeOH/에테르로부터 제결정하여 62.7 mg 의 생성물을 수득했다. M+1 501.3 계산치 501.16 MeI (45 μl, 0.72 mmol) was diluted with N- {4- (4-t-butyloxycarbonyl-1,4-diazepane-1-yl) -2-[(phenylsulfonyl) amino] phenyl} benzenesulphone To a mixture of amide (0.189 g, 0.36 mmol) and K 2 CO 3 (0.124, 0.90 mmol) in acetone (25 mL). The mixture was stirred at rt for 2 h and filtered to remove solvent. Purification by column chromatography (DCM / MeOH / heptane 4: 1: 15) gave N- {4- (4-t-butyloxycarbonyl-1,4-diazepan-1-yl) -2- [methyl (Phenylsulfonyl) -amino] phenyl} benzenesulfonamide was obtained as a colorless oil. Boc-deprotection was performed by dissolving the compound in a small amount of MeOH and adding HCl / ether. The solvent was removed and the residue was recrystallized from MeOH / ether to give 62.7 mg of product. M + 1 501.3 calc.501.16

반응식 3Scheme 3

N-{2-아미노-5-(4-t-부틸옥시카르보닐-1,4-디아제판-1-일)-페닐}메탄술폰아 미드 (134 mg, 0.35 mmol) 및 피리딘 (250 ㎕, 3.14 mmol) 의 DCM (7 mL) 중 용액에, 술포닐클로라이드 (0.455 mmol) 를 첨가했다. 실온에서 2 시간 후, 용매를 제거했다. 칼럼 크로마토그래피 (CH2Cl2/MeOH/헵탄, 4:1:15) 에 의한 정제에 이어, 잔사를 소량의 MeOH 에 용해하고 HCl/에테르를 첨가함으로써 수행되는 Boc-탈보호를 수행했다. 혼합물을 실온에서 0.5 시간 동안 정치시킨 후, 용매를 제거했다. 재결정 (MeOH/에테르) 으로 최종 생성물을 수득했다. N- {2-amino-5- (4-t-butyloxycarbonyl-1,4-diazepane-1-yl) -phenyl} methanesulfonamide (134 mg, 0.35 mmol) and pyridine (250 μl, 3.14 mmol) was added to a solution in DCM (7 mL), sulfonylchloride (0.455 mmol). After 2 hours at room temperature, the solvent was removed. Purification by column chromatography (CH 2 Cl 2 / MeOH / heptane, 4: 1: 15) was followed by Boc-deprotection performed by dissolving the residue in a small amount of MeOH and adding HCl / ether. The mixture was left at room temperature for 0.5 hours before the solvent was removed. Recrystallization (MeOH / ether) gave the final product.

실시예 39 Example 39

N-{4-(1,4-디아제판-1-일)-2-[(메틸술포닐)아미노]페닐}-1-나프탈렌술폰아미드 히드로클로라이드 (반응식 3)N- {4- (1,4-diazepane-1-yl) -2-[(methylsulfonyl) amino] phenyl} -1-naphthalenesulfonamide hydrochloride (Scheme 3)

화합물을, N-{2-아미노-5-(4-t-부틸옥시카르보닐-1,4-디아제판-1-일)-페닐}메탄술폰아미드 및 1-나프탈렌술포닐클로라이드 (103 mg, 0.455 mmol) 로부터 합성하여, Boc-탈보호 전에 150 mg 의 자주색 고체를 수득했다. M+1 475.1 계산치 474.14 The compound was prepared with N- {2-amino-5- (4-t-butyloxycarbonyl-1,4-diazepane-1-yl) -phenyl} methanesulfonamide and 1-naphthalenesulfonylchloride (103 mg, 0.455 mmol) to give 150 mg of a purple solid before Boc-deprotection. M + 1 475.1 calc. 474.14

실시예 40 Example 40

N-{4-(1,4-디아제판-1-일)-2-[(메틸술포닐)아미노]페닐}-2-나프탈렌술폰아미드 히드로클로라이드 (반응식 3)N- {4- (1,4-diazepane-1-yl) -2-[(methylsulfonyl) amino] phenyl} -2-naphthalenesulfonamide hydrochloride (Scheme 3)

화합물을, N-{2-아미노-5-(4-t-부틸옥시카르보닐-1,4-디아제판-1-일)-페닐}메탄술폰아미드 및 2-나프탈렌술포닐클로라이드 (103 mg, 0.455 mmol) 로부터 합성하여, Boc-탈보호 전 120 mg 의 자주색 고체를 수득했다. M+1 475.1 계산치 474.14 The compound was prepared with N- {2-amino-5- (4-t-butyloxycarbonyl-1,4-diazepane-1-yl) -phenyl} methanesulfonamide and 2-naphthalenesulfonylchloride (103 mg, 0.455 mmol) to give 120 mg of a purple solid before Boc-deprotection. M + 1 475.1 calc. 474.14

실시예 41 Example 41

N-{4-(1,4-디아제판-1-일)-2-[(메틸술포닐)아미노]페닐}-4-플루오로벤젠술폰아미드 히드로클로라이드 (반응식 3)N- {4- (1,4-diazepane-1-yl) -2-[(methylsulfonyl) amino] phenyl} -4-fluorobenzenesulfonamide hydrochloride (Scheme 3)

화합물을, N-{2-아미노-5-(4-t-부틸옥시카르보닐-1,4-디아제판-1-일)-페닐}메탄술폰아미드 및 4-플루오로벤젠술포닐클로라이드 (89 mg, 0.455 mmol) 로부터 합성하여, Boc-탈보호 전 170 mg 의 자주색 고체를 수득했다. M+1 443.1 계산치 443.11. The compound was prepared from N- {2-amino-5- (4-t-butyloxycarbonyl-1,4-diazepan-1-yl) -phenyl} methanesulfonamide and 4-fluorobenzenesulfonylchloride (89 mg, 0.455 mmol) to give 170 mg of a purple solid before Boc-deprotection. M + 1 443.1 calcd 443.11.

실시예 42 Example 42

N-{4-(1,4-디아제판-1-일)-2-(메틸술포닐)아미노]페닐}-4-니트로벤젠술폰아미드 히드로클로라이드 (반응식 3)N- {4- (1,4-diazepane-1-yl) -2- (methylsulfonyl) amino] phenyl} -4-nitrobenzenesulfonamide hydrochloride (Scheme 3)

화합물을, N-{2-아미노-5-(4-t-부틸옥시카르보닐-1,4-디아제판-1-일)-페닐}메탄술폰아미드 및 4-니트로벤젠술포닐클로라이드 (101 mg, 0.455 mmol) 로부터 일반 방법 3 에 따라 합성하여, Boc-탈보호 전 118 mg 의 자주색 고체를 수득했다. M+1 470.1 계산치 470.11. The compound was diluted with N- {2-amino-5- (4-t-butyloxycarbonyl-1,4-diazepan-1-yl) -phenyl} methanesulfonamide and 4-nitrobenzenesulfonylchloride (101 mg , 0.455 mmol), according to General Method 3 to give 118 mg of a purple solid before Boc-deprotection. M + 1 470.1 calcd 470.11.

실시예 43Example 43

N-{4-(1,4-디아제판-1-일)-2-[(메틸술포닐)아미노]페닐}-3-(트리플루오로메틸)벤젠술폰아미드 히드로클로라이드 (반응식 3)N- {4- (1,4-diazepane-1-yl) -2-[(methylsulfonyl) amino] phenyl} -3- (trifluoromethyl) benzenesulfonamide hydrochloride (Scheme 3)

화합물을 N-{2-아미노-5-(4-t-부틸옥시카르보닐-1,4-디아제판-1-일)-페닐}메탄술폰아미드 및 3-트리플루오로메틸벤젠술포닐클로라이드 (111 mg, 0.455 mmol) 로부터 합성하여, Boc-탈보호 전 145 mg 의 자주색 고체를 수득했다. M+1 493.1 계산치 493.11. The compound was treated with N- {2-amino-5- (4-t-butyloxycarbonyl-1,4-diazepan-1-yl) -phenyl} methanesulfonamide and 3-trifluoromethylbenzenesulfonylchloride ( 111 mg, 0.455 mmol) gave 145 mg of a purple solid before Boc-deprotection. M + 1 493.1 calcd 493.11.

실시예 44 Example 44

N-{4-(1,4-디아제판-1-일)-2-[(메틸술포닐)아미노]페닐}-2-메틸벤젠술폰아미드 히드로클로라이드 (반응식 3)N- {4- (1,4-diazepane-1-yl) -2-[(methylsulfonyl) amino] phenyl} -2-methylbenzenesulfonamide hydrochloride (Scheme 3)

화합물을 N-{2-아미노-5-(4-t-부틸옥시카르보닐-1,4-디아제판-1-일)-페닐} 메탄술폰아미드 및 o-톨루엔술포닐클로라이드 (87 mg, 0.455 mmol) 로부터 합성하여, Boc-탈보호 전 175 mg 의 자주색 고체를 수득했다. M+1 439.2 계산치 438.14The compound was diluted with N- {2-amino-5- (4-t-butyloxycarbonyl-1,4-diazepan-1-yl) -phenyl} methanesulfonamide and o-toluenesulfonylchloride (87 mg, 0.455 mmol) to give 175 mg of a purple solid before Boc-deprotection. M + 1 439.2 calculated 438.14

실시예 45 Example 45

N-{4-(1,4-디아제판-1-일)-2-[(메틸술포닐)아미노]페닐}-4-(트리플루오로메톡시)벤젠술폰아미드 히드로클로라이드 (반응식 3)N- {4- (1,4-diazepane-1-yl) -2-[(methylsulfonyl) amino] phenyl} -4- (trifluoromethoxy) benzenesulfonamide hydrochloride (Scheme 3)

화합물을 N-{2-아미노-5-(4-t-부틸옥시카르보닐-1,4-디아제판-1-일)-페닐}메탄술폰아미드 및 4-트리플루오로메톡시벤젠술포닐클로라이드 (119 mg, 0.455 mmol) 로부터 합성하여 140 mg 를 자주색 고체로서 수득했다. M+1 509.1 계산치 509.11. The compound was treated with N- {2-amino-5- (4-t-butyloxycarbonyl-1,4-diazepan-1-yl) -phenyl} methanesulfonamide and 4-trifluoromethoxybenzenesulfonylchloride ( 119 mg, 0.455 mmol) to give 140 mg as a purple solid. M + 1 509.1 calc.509.11.

실시예 46 Example 46

N-{4-(1,4-디아제판-1-일)-2-[(메틸술포닐)아미노]페닐]-3,5-디메틸-4-이속사졸술폰아미드 히드로클로라이드 (반응식 3)N- {4- (1,4-diazepane-1-yl) -2-[(methylsulfonyl) amino] phenyl] -3,5-dimethyl-4-isoxazolesulfonamide hydrochloride (Scheme 3)

화합물을 N-{2-아미노-5-(4-t-부틸옥시카르보닐-1,4-디아제판-1-일)-페닐} 메탄술폰아미드 및 3,5-디메틸이속사졸 술포닐클로라이드 (89 mg, 0.455 mmol) 로 부터 합성하여 120 mg 의 자주색 고체를 수득했다. M+1 444.2 계산치 444.13.The compound was converted to N- {2-amino-5- (4-t-butyloxycarbonyl-1,4-diazepane-1-yl) -phenyl} methanesulfonamide and 3,5-dimethylisoxazole sulfonylchloride Synthesis from (89 mg, 0.455 mmol) gave 120 mg of a purple solid. M + 1 444.2 calcd 444.13.

실시예 47 Example 47

N-{4-(1,4-디아제판-1-일)-2-[(메틸술포닐)아미노]페닐}-3-메톡시벤젠술폰아미드 히드로클로라이드 (반응식 3)N- {4- (1,4-diazepane-1-yl) -2-[(methylsulfonyl) amino] phenyl} -3-methoxybenzenesulfonamide hydrochloride (Scheme 3)

화합물을 N-{2-아미노-5-(4-t-부틸옥시카르보닐-1,4-디아제판-1-일)-페닐}메탄술폰아미드 및 3-메톡시벤젠술포닐클로라이드 (94 mg, 0.455 mmol) 로부터 합성하여 160 mg 를 자주색 고체로서 수득했다. M+1 455.2 계산치 455.13 The compound was diluted with N- {2-amino-5- (4-t-butyloxycarbonyl-1,4-diazepan-1-yl) -phenyl} methanesulfonamide and 3-methoxybenzenesulfonylchloride (94 mg , 0.455 mmol) to give 160 mg as a purple solid. M + 1 455.2 calc. 455.13

중간체 11 Intermediate 11

tert-부틸-4-{4-{[(4-메틸페닐)술포닐]아미노}-3-[(메틸술포닐)아미노]페닐}-1,4-디아제판-1-카르복실레이트 (반응식 2, 방법 4)tert-butyl-4- {4-{[(4-methylphenyl) sulfonyl] amino} -3-[(methylsulfonyl) amino] phenyl} -1,4-diazepane-1-carboxylate (Scheme 2 , Method 4)

tert-부틸 4-{4-니트로-3-[(메틸술포닐)아미노]페닐}-1,4-디아제판-1-카르복실레이트 (1 g, 2.4 mmol) 을 THF (20 mL) 및 메탄올 (2 mL) 에 용해시켰다. 라니-니켈 (0.2 g) 을 첨가한 후, 히드라진 수화물 (0.2 mL) 을 첨가했다. 질소를 방출시키고 혼합물을 1 시간 동안 교반했다. TLC (CH2Cl2:MeOH 9:1) 에 의해 반응이 불완전한 것으로 나타나면, 0.1 mL 의 히드라진 수화물을 첨가했다. 1 시간 후, 반응 혼합물을 실리카겔의 층 상에 흡수시키고, CH2Cl2:MeOH:NH40H (9:1:0.01, 150 mL) 로 용출했다. 용매는 증발시켜 제거하고, 톨루엔 (100 mL) 을 첨가하고 증발시켜 임의의 물 및 히드라진을 제거했다. 미정제 아민 (0.9 g) 을 아세토니트릴 (20 mL) 에 용해시켰다. 질소 하에 상기 용액에 디메틸아미노피리딘 (0.32 g) 및 톨루엔술포닐 클로라이드 (0.51 g) 를 첨가하고, 혼합물을 3 시간 동안 교반했다. 용액을 물 (100 mL) 에 붓고, 에틸 아세테이트 (30 mL) 로 추출했다. 유기 추출물을 물로 세척하고, MgSO4 상에서 건조시키고 증발시켜 0.83 g 의 미정제 생성물을 수득해, 플래쉬 크로마토그래피 (EtOAc:휘발유 1:1) 로 정제했다. 수율 0.53 g (41%)tert-butyl 4- {4-nitro-3-[(methylsulfonyl) amino] phenyl} -1,4-diazepane-1-carboxylate (1 g, 2.4 mmol) in THF (20 mL) and methanol In 2 mL). Raney-nickel (0.2 g) was added followed by hydrazine hydrate (0.2 mL). Nitrogen was released and the mixture was stirred for 1 hour. If the reaction was incomplete by TLC (CH 2 Cl 2 : MeOH 9: 1), 0.1 mL of hydrazine hydrate was added. After 1 hour, the reaction mixture was absorbed onto a layer of silica gel and eluted with CH 2 Cl 2 : MeOH: NH 4 0H (9: 1: 0.01, 150 mL). The solvent was removed by evaporation, toluene (100 mL) was added and evaporated to remove any water and hydrazine. Crude amine (0.9 g) was dissolved in acetonitrile (20 mL). Dimethylaminopyridine (0.32 g) and toluenesulfonyl chloride (0.51 g) were added to the solution under nitrogen, and the mixture was stirred for 3 hours. The solution was poured into water (100 mL) and extracted with ethyl acetate (30 mL). The organic extract was washed with water, dried over MgSO 4 and evaporated to yield 0.83 g of crude product which was purified by flash chromatography (EtOAc: Petrol 1: 1). Yield 0.53 g (41%)

Figure 112003042468427-pct00069
Figure 112003042468427-pct00069

실시예 48 Example 48

N-{4-(1,4-디아제판-1-일)-2-[(메틸술포닐)아미노]페닐}-4-메틸벤젠술폰아미드 히드로클로라이드 (PHA 516123A) N- {4- (1,4-diazepane-1-yl) -2-[(methylsulfonyl) amino] phenyl} -4-methylbenzenesulfonamide hydrochloride (PHA 516123A)

tert-부틸4-{4-{[(4-메틸페닐)술포닐]아미노}-3-[(메틸술포닐)아미노]페닐}-1,4-디아제판-1-카르복실레이트 (0.5 g) 를 메탄올 (15 mL) 에 용해했다. HCl 의 에틸 아세테이트 (1N, 25 mL) 중 용액을 첨가하고, 혼합물을 2 시간 동안 교반했다. 에테르 (200 mL) 를 첨가하고, 혼합물을 3 시간 동안 교반해 완전히 침전시켰다. 생성물을 여과하여 회수하고 에테르로 세척하고 건조시켰다. 수율 0.43 g (98%).tert-butyl4- {4-{[(4-methylphenyl) sulfonyl] amino} -3-[(methylsulfonyl) amino] phenyl} -1,4-diazepane-1-carboxylate (0.5 g) Was dissolved in methanol (15 mL). A solution of HCl in ethyl acetate (1N, 25 mL) was added and the mixture was stirred for 2 hours. Ether (200 mL) was added and the mixture was stirred for 3 hours to allow complete precipitation. The product was collected by filtration, washed with ether and dried. Yield 0.43 g (98%).

Figure 112003042468427-pct00070
Figure 112003042468427-pct00070

중간체 12 Intermediate 12

N-에틸-N-(5-플루오로-2-니트로페닐)메탄술폰아미드 (반응식 2, 방법 4)N-ethyl-N- (5-fluoro-2-nitrophenyl) methanesulfonamide (Scheme 2, method 4)

N-에틸-메탄술폰아미드 (Mijs 등, J. Chem. Soc. Chem. Com. 1972 p412) (5 g, 40.6 mmol) 를, 수소화나트륨 (1.9 g, 미네랄 오일 중 55%) 의 무수 DMF (100 mL) 중 현탁액에 질소 하에서 첨가했다. 혼합물을 1 시간 동안 55℃ 까지 가온하고, 2,4-디플루오로니트로벤젠 (4.4 mL) 을 적가했다. 반응물을 60℃ 에서 밤새 교반하고, 물 (500 mL) 을 붓고, 생성물을 CH2Cl2 (5 ×1OOmL) 로 추출했다. 유기 추출물을 물로 세척하고, MgSO4 상에서 건조하고 증발시켜 오일성 생성물을 수득했다. 잔류 DMF 를 휘발유로 연화하여 제거했다. 미정제 생성물을 플래쉬 크로마토그래피 (에틸 아세테이트:휘발유 1: 1) 로 정제하여 원하는 생성물을 수득해 에탄올로부터 재결정했다. 수율 3.5 g (33%). N-ethyl-methanesulfonamide (Mijs et al., J. Chem. Soc. Chem. Com. 1972 p412) (5 g, 40.6 mmol) was added to anhydrous DMF (100 g) of sodium hydride (1.9 g, 55% in mineral oil). mL) to suspension in nitrogen. The mixture was warmed to 55 ° C. for 1 h and 2,4-difluoronitrobenzene (4.4 mL) was added dropwise. The reaction was stirred at 60 ° C. overnight, water (500 mL) was poured and the product extracted with CH 2 Cl 2 (5 × 10 mL). The organic extract was washed with water, dried over MgSO 4 and evaporated to give an oily product. The residual DMF was removed by softening with gasoline. The crude product was purified by flash chromatography (ethyl acetate: gasoline 1: 1) to afford the desired product and recrystallized from ethanol. Yield 3.5 g (33%).

Figure 112003042468427-pct00071
Figure 112003042468427-pct00071

중간체 13 Intermediate 13

tert-부틸 4-{3-[에틸(메틸술포닐)아미노]-4-니트로페닐}-1,4-디아제판-1-카 르복실레이트 (반응식 2, 방법 4) tert-butyl 4- {3- [ethyl (methylsulfonyl) amino] -4-nitrophenyl} -1,4-diazepane-1-carboxylate (Scheme 2, method 4)

N-에틸-N-(5-플루오로-2-니트로페닐)메탄술폰아미드 (3.2 g, 12.2 mmol), tert-부틸 1-호모피페라진카르복실레이트 (2.5 g) 및 탄산칼륨 (2 g) 을 함께 DMSO 중에서 50℃ 로 5 시간 동안 가열했다. 용액을 냉각시켜, 500 ml 의 물에 부었다. 고체 생성물을 여과로 수집하고, 물로 세척하여 건조시켰다. 생성물을 플래쉬 크로마토그래피 (에틸 아세테이트:휘발유 1: 1) 로 정제했다.수율 2.6g (48%) N-ethyl-N- (5-fluoro-2-nitrophenyl) methanesulfonamide (3.2 g, 12.2 mmol), tert-butyl 1-homopiperazinecarboxylate (2.5 g) and potassium carbonate (2 g) Were heated together at 50 ° C. in DMSO for 5 h. The solution was cooled down and poured into 500 ml of water. The solid product was collected by filtration, washed with water and dried. The product was purified by flash chromatography (ethyl acetate: petrol 1: 1). Yield 2.6 g (48%)

Figure 112003042468427-pct00072
Figure 112003042468427-pct00072

N-{4-(1,4-디아제판-1-일)-2-[에틸(메틸술포닐)아미노]페닐}술폰아미드의 제조Preparation of N- {4- (1,4-diazepane-1-yl) -2- [ethyl (methylsulfonyl) amino] phenyl} sulfonamide

tert-부틸 4-{3-[에틸(메틸술포닐)아미노]-4-니트로페닐}-1,4-디아제판-1-카르복실레이트 (2.5 g, 5.7 mmol) 을 THF (50 mL) 및 메탄올 (5 mL) 중에 용해시켰다. 라니-니켈 (0.5 g) 을 첨가한 후 히드라진 수화물 (0.5 mL) 을 첨가했다. 질소를 배출시키고, 혼합물을 1 시간 동안 교반했다. 반응 혼합물을 실리카 겔 층 상에 흡수시키고, CH2Cl2:MeOH:NH40H (9:1:0.01, 200 mL) 로 용출했다. 용매를 증발시켜 제거하고, 톨루엔 (200 mL) 을 첨가하고 증발시켜, 임의의 물 및 히드라진을 제거했다. 미정제 아민 (2.15 g) 을 아세토니트릴 (50 mL) 중에 디메틸아미노피리딘 (0.8 g) 과 함께 용해시켰다. 상기 용액을 3 부로 나누었다. 각각의 부에 술포닐 클로라이드 (2.2 mmol) 를 첨가하고, 혼합물을 밤새 40℃ 에서 교반했 다. 반응물에 물 (150 mL) 을 첨가하여 워크업하고, 생성물을 에틸 아세테이트로 추출하고, 물로 세척하고, MgSO4 상에서 건조시키고 증발시켰다. 각각의 미정제 boc-보호 생성물을 플래쉬 크로마토그래피 (에틸 아세테이트:휘발유 1:1) 로 정제했다. 이어서, 이들을 메탄올 (10 mL) 중에 용해시키고, HCl 의 에틸 아세테이트 (1 N, 50 mL) 중 용액을 첨가하고 2 시간 동안 교반하여 직접 탈보호했다. 생성물을 에테르 (500 mL) 로 침전시키고, 여과로 수집하고 진공 하에 건조시켰다. 수득한 생성물은 하기이다: tert-butyl 4- {3- [ethyl (methylsulfonyl) amino] -4-nitrophenyl} -1,4-diazepane-1-carboxylate (2.5 g, 5.7 mmol) was diluted with THF (50 mL) and It was dissolved in methanol (5 mL). Raney-nickel (0.5 g) was added followed by hydrazine hydrate (0.5 mL). Nitrogen was discharged and the mixture was stirred for 1 hour. The reaction mixture was taken up on a silica gel layer and eluted with CH 2 Cl 2 : MeOH: NH 4 0H (9: 1: 0.01, 200 mL). The solvent was removed by evaporation, toluene (200 mL) was added and evaporated to remove any water and hydrazine. Crude amine (2.15 g) was dissolved in acetonitrile (50 mL) with dimethylaminopyridine (0.8 g). The solution was divided into 3 parts. Sulfonyl chloride (2.2 mmol) was added to each portion and the mixture was stirred at 40 ° C. overnight. The reaction was worked up by addition of water (150 mL) and the product was extracted with ethyl acetate, washed with water, dried over MgSO 4 and evaporated. Each crude boc-protection product was purified by flash chromatography (ethyl acetate: petrol 1: 1). They were then dissolved in methanol (10 mL) and a solution of HCl in ethyl acetate (1 N, 50 mL) was added and stirred for 2 hours to deprotect directly. The product was precipitated with ether (500 mL), collected by filtration and dried under vacuum. The product obtained is:

실시예 49 Example 49

N-{4-(1,4-디아제판-1-일)-2-[에틸(메틸술포닐)-아미노]페닐}-4-메틸벤젠술폰아미드 히드로클로라이드 (반응식 2,방법 4) 은, 톨루엔 술포닐 클로라이드로부터 수득했다: 수율 0.36 g N- {4- (1,4-diazepane-1-yl) -2- [ethyl (methylsulfonyl) -amino] phenyl} -4-methylbenzenesulfonamide hydrochloride (Scheme 2, method 4) is Obtained from toluene sulfonyl chloride: yield 0.36 g

Figure 112003042468427-pct00073
Figure 112003042468427-pct00073

실시예 50 Example 50

N-{4-(1,4-디아제판-1-일)-2-[에틸-(메틸술포닐)-아미노]페닐}-3,4-디메톡시벤젠술폰아미드 히드로클로라이드 (반응식 2, 방법 4) 은, 3,4-디메톡시벤젠술포닐 클로라이드로부터 수득했다: 수율 0.43 g N- {4- (1,4-diazepane-1-yl) -2- [ethyl- (methylsulfonyl) -amino] phenyl} -3,4-dimethoxybenzenesulfonamide hydrochloride (Scheme 2, method 4) was obtained from 3,4-dimethoxybenzenesulfonyl chloride: yield 0.43 g

Figure 112003042468427-pct00074
Figure 112003042468427-pct00074

실시예 51 Example 51

N-{4-(1,4-디아제판-1-일)-2-[에틸(메틸-술포닐)아미노]페닐}-8-퀴놀린술폰아미드 히드로클로라이드 (반응식 2, 방법 4) 은 8-퀴놀린 술포닐 클로라이드로부터 수득했다: 수율 0.46 g N- {4- (1,4-diazepane-1-yl) -2- [ethyl (methyl-sulfonyl) amino] phenyl} -8-quinolinesulfonamide hydrochloride (Scheme 2, method 4) was 8- Obtained from quinoline sulfonyl chloride: yield 0.46 g

Figure 112003042468427-pct00075
Figure 112003042468427-pct00075

중간체 14 Intermediate 14

N-(5-플루오로-2-니트로페닐)메탄술폰아미드 (반응식 2, 방법 4)N- (5-fluoro-2-nitrophenyl) methanesulfonamide (Scheme 2, method 4)

2,4-디-니트로벤젠 (5.5 mL, 50 mmol), 메탄술폰아미드 (4.75 g, 50 mmol) 및 탄산칼륨 (1O g) 을 함께 DMSO (1OO mL) 중에서 80℃ 로 밤새 교반했다. 물 (3OO mL) 을 첨가한 후 염산 (1 N, 3OOmL) 을 첨가했다. 고체 생성물을 여과로 수집하고, 물로 세척하고 건조시켰다. 수율 9.57g (82%) 2,4-Di-nitrobenzene (5.5 mL, 50 mmol), methanesulfonamide (4.75 g, 50 mmol) and potassium carbonate (10 g) were stirred together at 80 ° C. overnight in DMSO (100 mL). Water (3OO mL) was added followed by hydrochloric acid (1N, 3OOmL). The solid product was collected by filtration, washed with water and dried. Yield 9.57 g (82%)

Figure 112003042468427-pct00076
Figure 112003042468427-pct00076

중간체 15 Intermediate 15

N-(5-플루오로-2-니트로페닐)-N-메틸메탄술폰아미드 (반응식 2, 방법 4)N- (5-fluoro-2-nitrophenyl) -N-methylmethanesulfonamide (Scheme 2, method 4)

N-(5-플루오로-2-니트로페닐)메탄술폰아미드 화합물 (5 g, 21 mmol), 메틸 요오다이드 (3 mL) 및 탄산칼륨 (10 g) 을 함께 DMSO (1OO mL) 중에서 80℃ 에서 밤새 교반했다. 반응이 완결되지 않으면, 1 mL 의 메틸 요오다이드를 추가로 첨가했다. 80℃ 에서 추가로 24 시간 후, 물 (1,OOO mL) 을 첨가했다. 용액을 소량의 끈끈한 잔사로부터 따라냈다. 생성물을 수용액에서 결정화하고 (48 시간), 여과하여 수집하고, 물로 세척하고 건조시켰다. 수율 3.3g (63%); N- (5-fluoro-2-nitrophenyl) methanesulfonamide compound (5 g, 21 mmol), methyl iodide (3 mL) and potassium carbonate (10 g) together were 80 ° C. in DMSO (10 mL) Stirred overnight. If the reaction was not complete, 1 mL of methyl iodide was further added. After a further 24 hours at 80 ° C., water (1, OOO mL) was added. The solution was poured from a small amount of sticky residue. The product was crystallized in aqueous solution (48 hours), collected by filtration, washed with water and dried. Yield 3.3 g (63%);

Figure 112003042468427-pct00077
Figure 112003042468427-pct00077

중간체 16 Intermediate 16

tert-부틸-4-{3-[메틸(메틸술포닐)아미노]-4-니트로페닐]-1,4-디아제판-1-카르복실레이트 (반응식 2, 방법 4) tert-butyl-4- {3- [methyl (methylsulfonyl) amino] -4-nitrophenyl] -1,4-diazepane-1-carboxylate (Scheme 2, method 4)

N-(5-플루오로-2-니트로페닐)-N-메틸메탄술폰아미드 (3.1 g, 12.5 mmol), tert-부틸 1-호모피페라진카르복실레이트 (2.5 g) 및 탄산칼륨 (2 g) 을 함께 DMSO (50 mL) 중에서 80℃ 로 밤새 가열했다. 용액을 냉각시키고, 500 mL 의 물에 부었다. 고체 생성물을 여과로 수집하고, 물로 세척하고 건조시켰다. 수율 4.6 g (86%); N- (5-fluoro-2-nitrophenyl) -N-methylmethanesulfonamide (3.1 g, 12.5 mmol), tert-butyl 1-homopiperazinecarboxylate (2.5 g) and potassium carbonate (2 g) Were heated together at 80 ° C. overnight in DMSO (50 mL). The solution was cooled down and poured into 500 mL of water. The solid product was collected by filtration, washed with water and dried. Yield 4.6 g (86%);

Figure 112003042468427-pct00078
Figure 112003042468427-pct00078

N-{4-(1,4-디아제판-1-일)-2-[메틸(메틸술포닐)아미노]페닐}술폰아미드의 제조Preparation of N- {4- (1,4-diazepane-1-yl) -2- [methyl (methylsulfonyl) amino] phenyl} sulfonamide

tert-부틸-4-{3-[메틸(메틸술포닐)아미노]-4-니트로페닐]-1,4-디아제판-1-카르복실레이트 (2.5 g, 5.7 mmol) 을 THF (50 mL) 및 메탄올 (5 mL) 중에 용해했다. 라니 니켈 (0.5 g) 을 첨가한 후, 히드라진 수화물 (0.5 mL) 을 첨가했다. 질소 를 배출하고, 혼합물을 1 시간 동안 교반했다. 반응 혼합물을 실리카 겔 층 상에 흡수시키고, CH2Cl2:MeOH:NH40H (9:1:0.01, 200 mL) 로 용출했다. 용매를 증발로 제거하고, 톨루엔 (200 mL) 을 첨가하고 증발시켜, 임의의 물 및 히드라진을 제거했다. 미정제 아민 (2.36 g) 을 디메틸아미노피리딘 (0.8 g) 이 있는 아세토니트릴 (50 mL) 중에 용해시켰다. 상기 용액을 6 부로 나누었다. 상기 중 3 부에 술포닐 클로라이드 (1.1 mmol) 를 첨가하고, 혼합물을 밤새 40℃ 에서 교반했다. 반응물에 에틸 아세테이트 (50 mL) 를 첨가하고, 식염수 및 물로 세척하고, MgSO4 상에서 건조시키고 증발시켜 워크업했다. 각각의 미정제 boc-보호 생성물을 플래쉬 크로마토그래피 (에틸 아세테이트:휘발유 2:1) 로 정제했다. 이어서, 이들을 메탄올 (1O mL) 중에 용해하고, HCl 의 에틸 아세테이트 (1 N, 50 mL) 중 용액을 첨가하고 2 시간 동안 교반함으로써 직접 탈보호했다. 생성물을 에테르 (500 mL) 로 침전시키고, 여과로 수집하고 진공 하에 건조시켰다. tert-butyl-4- {3- [methyl (methylsulfonyl) amino] -4-nitrophenyl] -1,4-diazepane-1-carboxylate (2.5 g, 5.7 mmol) in THF (50 mL) And dissolved in methanol (5 mL). Raney nickel (0.5 g) was added followed by hydrazine hydrate (0.5 mL). Nitrogen was discharged and the mixture was stirred for 1 hour. The reaction mixture was taken up on a silica gel layer and eluted with CH 2 Cl 2 : MeOH: NH 4 0H (9: 1: 0.01, 200 mL). The solvent was removed by evaporation, toluene (200 mL) was added and evaporated to remove any water and hydrazine. Crude amine (2.36 g) was dissolved in acetonitrile (50 mL) with dimethylaminopyridine (0.8 g). The solution was divided into 6 parts. Sulfonyl chloride (1.1 mmol) was added to 3 parts of the above, and the mixture was stirred at 40 ° C. overnight. Ethyl acetate (50 mL) was added to the reaction, washed with brine and water, dried over MgSO 4 and worked up by evaporation. Each crude boc-protected product was purified by flash chromatography (ethyl acetate: petrol 2: 1). These were then dissolved in methanol (10 mL) and deprotected directly by adding a solution of HCl in ethyl acetate (1 N, 50 mL) and stirring for 2 hours. The product was precipitated with ether (500 mL), collected by filtration and dried under vacuum.

수득한 생성물은 하기이다: The product obtained is as follows:

실시예 52 Example 52                 

N-{4-(1,4-디아제판-1-일)-2-[메틸(메틸술포닐)-아미노]페닐}-4-메틸벤젠술폰아미드 히드로클로라이드 (반응식 2, 방법 4) 를 톨루엔 술포닐 클로라이드로부터 수득했다: 수율 0.18 g N- {4- (1,4-diazepane-1-yl) -2- [methyl (methylsulfonyl) -amino] phenyl} -4-methylbenzenesulfonamide hydrochloride (Scheme 2, method 4) toluene Obtained from sulfonyl chloride: yield 0.18 g

Figure 112003042468427-pct00079
Figure 112003042468427-pct00079

실시예 53 Example 53

N-{4-(1,4-디아제판-1-일)-2-[메틸-(메틸-술포닐)아미노]페닐}-나프탈렌-2-술폰아미드 히드로클로라이드 (반응식 2, 방법 4) 를 2-나프탈렌술포닐 클로라이드로부터 수득했다: 수율 0.09 g N- {4- (1,4-diazepane-1-yl) -2- [methyl- (methyl-sulfonyl) amino] phenyl} -naphthalene-2-sulfonamide hydrochloride (Scheme 2, method 4) Obtained from 2-naphthalenesulfonyl chloride: yield 0.09 g

Figure 112003042468427-pct00080
Figure 112003042468427-pct00080

실시예 54 Example 54

N-{4-(1,4-디아제판-1-일)-2-[메틸(메틸술포닐)아미노]페닐}-5-(2-피리디닐) 티오펜술폰아미드 히드로클로라이드 (반응식 2, 방법 4) 를 5-(2-피리디닐)티오펜 술포닐 클로라이드로부터 수득했다: 수율 0.12 g N- {4- (1,4-diazepane-1-yl) -2- [methyl (methylsulfonyl) amino] phenyl} -5- (2-pyridinyl) thiophensulfonamide hydrochloride (Scheme 2, Method 4) was obtained from 5- (2-pyridinyl) thiophene sulfonyl chloride: yield 0.12 g

Figure 112003042468427-pct00081
Figure 112003042468427-pct00081

반응식 3Scheme 3

N-{2-아미노-5-(4-t-부틸옥시카르보닐-1,4-디아제판-1-일)-페닐}벤젠술폰아미드 (92.5 mg, 0.207 mmol) 및 피리딘 (131 ㎕, 1.6 mmol) 의 DCM (7 mL) 중 용액에, 술포닐클로라이드 (0.27 mmol) 를 첨가했다. 실온에서 2 시간 후, 용매를 제거했다. 칼럼 크로마토그래피 (CH2Cl2/MeOH/헵탄, 4:1:15) 에 의한 정제에 이어, 잔사를 소량의 MeOH 에 용해시키고 HCl/에테르를 첨가하는 Boc-탈보호에 적용시켰다. 혼합물을 실온에서 0.5 시간 동안 정치시킨 후, 용매를 제거했다. 재결정 (MeOH/에테르) 으로 최종 생성물을 수득했다. N- {2-amino-5- (4-t-butyloxycarbonyl-1,4-diazepane-1-yl) -phenyl} benzenesulfonamide (92.5 mg, 0.207 mmol) and pyridine (131 μl, 1.6 To a solution in mmol) of DCM (7 mL), sulfonylchloride (0.27 mmol) was added. After 2 hours at room temperature, the solvent was removed. Purification by column chromatography (CH 2 Cl 2 / MeOH / heptane, 4: 1: 15) was followed by Boc-deprotection, which dissolved the residue in a small amount of MeOH and added HCl / ether. The mixture was left at room temperature for 0.5 hours before the solvent was removed. Recrystallization (MeOH / ether) gave the final product.

실시예 55 Example 55

N-{4-(1,4-디아제판-1-일)-2-[(페닐술포닐)아미노]페닐}-1-나프탈렌술폰아미드 히드로클로라이드 (반응식 3)N- {4- (1,4-diazepane-1-yl) -2-[(phenylsulfonyl) amino] phenyl} -1-naphthalenesulfonamide hydrochloride (Scheme 3)

화합물을, N-{2-아미노-5-(4-t-부틸옥시카르보닐-1,4-디아제판-1-일)-페닐}벤젠술폰아미드 및 1-나프탈렌술포닐클로라이드 (61 mg, 0.27 mmol) 로부터 합성하 여 56 mg 의 자주색 고체를 수득했다. M+1 537.2 계산치 537.15The compound was prepared with N- {2-amino-5- (4-t-butyloxycarbonyl-1,4-diazepane-1-yl) -phenyl} benzenesulfonamide and 1-naphthalenesulfonylchloride (61 mg, 0.27 mmol) to give 56 mg of a purple solid. M + 1 537.2 calc 537.15

Figure 112003042468427-pct00082
Figure 112003042468427-pct00082

실시예 56 Example 56

N-{4-(1,4-디아제판-1-일)-2-[(페닐술포닐)아미노]페닐}-5-(디메틸아미노)-1-나프탈렌술폰아미드 히드로클로라이드 (반응식 3)N- {4- (1,4-diazepane-1-yl) -2-[(phenylsulfonyl) amino] phenyl} -5- (dimethylamino) -1-naphthalenesulfonamide hydrochloride (Scheme 3)

화합물을 N-{2-아미노-5-(4-t-부틸옥시카르보닐-1,4-디아제판-1-일)-페닐)벤젠술폰아미드 및 댄실클로라이드 (73 mg, 0.27 mmol) 로부터 합성하여 51 mg 의 자주색 고체를 수득했다. M+1 580.3 계산치 580.20;Compounds were synthesized from N- {2-amino-5- (4-t-butyloxycarbonyl-1,4-diazepane-1-yl) -phenyl) benzenesulfonamide and dansylchloride (73 mg, 0.27 mmol) To give 51 mg of a purple solid. M + 1 580.3 calc. 580.20;

Figure 112003042468427-pct00083
Figure 112003042468427-pct00083

실시예 57 Example 57

N-{4-(1,4-디아제판-1-일)-2-[(페닐술포닐)아미노]페닐}-8-퀴놀린술폰아미드 히드로클로라이드 (반응식 3) N- {4- (1,4-diazepane-1-yl) -2-[(phenylsulfonyl) amino] phenyl} -8-quinolinesulfonamide hydrochloride (Scheme 3)

화합물을 N-{2-아미노-5-(4-t-부틸옥시카르보닐-1,4-디아제판-1-일)-페닐}벤젠술폰아미드 및 8-퀴놀린술포닐클로라이드 (61 mg, 0.27 mmol) 로부터 합성하여, 34 mg 의 자주색 고체를 수득했다. M+1 538.2 계산치 538.15. The compound was diluted with N- {2-amino-5- (4-t-butyloxycarbonyl-1,4-diazepan-1-yl) -phenyl} benzenesulfonamide and 8-quinolinesulfonylchloride (61 mg, 0.27 mmol) to afford 34 mg of a purple solid. M + 1 538.2 calcd 538.15.

실시예 58 Example 58

N-{4-(1,4-디아제판-1-일)-2-[(페닐술포닐)아미노]페닐}-2,4,6-트리메틸벤젠술폰아미드 히드로클로라이드 (반응식 3)N- {4- (1,4-diazepane-1-yl) -2-[(phenylsulfonyl) amino] phenyl} -2,4,6-trimethylbenzenesulfonamide hydrochloride (Scheme 3)

화합물을 N-{2-아미노-5-(4-t-부틸옥시카르보닐-1,4-디아제판-1-일)-페닐}벤젠술폰아미드 및 2-메시틸렌술포닐클로라이드 (59 mg, 0.27 mmol) 로부터 합성하여 56 mg 의 자주색 고체를 수득했다. M+1 529.3 계산치 529.70;The compound was diluted with N- {2-amino-5- (4-t-butyloxycarbonyl-1,4-diazepan-1-yl) -phenyl} benzenesulfonamide and 2-mesitylenesulfonylchloride (59 mg, 0.27 mmol) to give 56 mg of a purple solid. M + 1 529.3 calc. 529.70;

Figure 112003042468427-pct00084
Figure 112003042468427-pct00084

실시예 59 Example 59

N-{4-(1,4-디아제판-1-일)-2-[(페닐술포닐)아미노]페닐}-4-메틸벤젠술폰아미드 히드로클로라이드 (반응식 3)N- {4- (1,4-diazepane-1-yl) -2-[(phenylsulfonyl) amino] phenyl} -4-methylbenzenesulfonamide hydrochloride (Scheme 3)

화합물을 N-{2-아미노-5-(4-t-부틸옥시카르보닐-1,4-디아제판-1-일)-페닐}벤젠술폰아미드 및 p-톨루엔술포닐클로라이드 (51 mg, 0.27 mmol) 로부터 합성하여, 22 mg 의 자주색 고체를 수득했다. M+1 501.3 계산치 501.15The compound was diluted with N- {2-amino-5- (4-t-butyloxycarbonyl-1,4-diazepan-1-yl) -phenyl} benzenesulfonamide and p-toluenesulfonylchloride (51 mg, 0.27 mmol) to give 22 mg of a purple solid. M + 1 501.3 calc.501.15

Figure 112003042468427-pct00085
Figure 112003042468427-pct00085

실시예 60 Example 60

N-[5-(1,4-디아제판-1-일)-2-({[(E)-2-페닐에테닐]술포닐}아미노)페닐]벤젠술폰아미드 히드로클로라이드 (반응식 3) N- [5- (1,4-diazepane-1-yl) -2-({[(E) -2-phenylethenyl] sulfonyl} amino) phenyl] benzenesulfonamide hydrochloride (Scheme 3)

화합물을 N-{2-아미노-5-(4-t-부틸옥시카르보닐-1,4-디아제판-1-일)-페닐}벤젠술폰아미드 및 베타-스티렌술포닐클로라이드 (55 mg, 0.27 mmol) 로부터 합성하여 Boc-탈보호 전에 12 mg 의 자주색 고체를 수득했다. M+1 513.6 계산치 512.15;The compound was diluted with N- {2-amino-5- (4-t-butyloxycarbonyl-1,4-diazepan-1-yl) -phenyl} benzenesulfonamide and beta-styrenesulfonylchloride (55 mg, 0.27 mmol) gave 12 mg of a purple solid before Boc-deprotection. M + 1 513.6 calc. 512.15;

Figure 112003042468427-pct00086
Figure 112003042468427-pct00086

실시예 61 Example 61

N-{4-(1,4-디아제판-1-일)-2-[(페닐술포닐)아미노]페닐}-2,5-디메톡시벤젠술폰아미드 히드로클로라이드 (반응식 3)N- {4- (1,4-diazepane-1-yl) -2-[(phenylsulfonyl) amino] phenyl} -2,5-dimethoxybenzenesulfonamide hydrochloride (Scheme 3)

화합물을 N-{2-아미노-5-(4-t-부틸옥시카르보닐-1,4-디아제판-1-일)-페닐}벤젠술폰아미드 및 2,5-디메톡시벤젠술포닐클로라이드 (64 mg, 0.27 mmol) 로부터 합성하여 14 mg 의 자주색 고체를 수득했다. M+1 547.3 계산치 547.16The compound was treated with N- {2-amino-5- (4-t-butyloxycarbonyl-1,4-diazepan-1-yl) -phenyl} benzenesulfonamide and 2,5-dimethoxybenzenesulfonylchloride ( 64 mg, 0.27 mmol) gave 14 mg of a purple solid. M + 1 547.3 calc 547.16

Figure 112003042468427-pct00087
Figure 112003042468427-pct00087

실시예 62 Example 62

N-{4-(1,4-디아제판-1-일)-2-[(페닐술포닐)아미노]페닐}-2-메틸벤젠술폰아미드 히드로클로라이드 (반응식 3) N- {4- (1,4-diazepane-1-yl) -2-[(phenylsulfonyl) amino] phenyl} -2-methylbenzenesulfonamide hydrochloride (Scheme 3)

화합물을 N-{2-아미노-5-(4-t-부틸옥시카르보닐-1,4-디아제판-1-일)-페닐}벤젠술폰아미드 및 o-톨루엔술포닐클로라이드 (51 mg, 0.269 mmol) 로부터 합성하여 18 mg 의 자주색 고체를 수득했다. M+1 501.3 계산치 501.15;The compound was diluted with N- {2-amino-5- (4-t-butyloxycarbonyl-1,4-diazepan-1-yl) -phenyl} benzenesulfonamide and o-toluenesulfonylchloride (51 mg, 0.269 mmol) gave 18 mg of a purple solid. M + 1 501.3 calcd 501.15;

Figure 112003042468427-pct00088
Figure 112003042468427-pct00088

실시예 63 Example 63                 

4-부톡시-N-{4-(1,4-디아제판-1-일)-2-[(페닐술포닐)아미노]페닐}벤젠술폰아미드 히드로클로라이드 (반응식 3)4-butoxy-N- {4- (1,4-diazepane-1-yl) -2-[(phenylsulfonyl) amino] phenyl} benzenesulfonamide hydrochloride (Scheme 3)

화합물을 N-{2-아미노-5-(4-t-부틸옥시카르보닐-1,4-디아제판-1-일)-페닐}벤젠술폰아미드 및 4-n-부톡시벤젠술포닐클로라이드 (67 mg, 0.269 mmol) 로부터 합성하여 27 mg 의 자주색 고체를 수득했다. M+1 559.4 계산치 559.20The compound was treated with N- {2-amino-5- (4-t-butyloxycarbonyl-1,4-diazepan-1-yl) -phenyl} benzenesulfonamide and 4-n-butoxybenzenesulfonylchloride ( 67 mg, 0.269 mmol) gave 27 mg of a purple solid. M + 1 559.4 calc.559.20

Figure 112003042468427-pct00089
Figure 112003042468427-pct00089

실시예 64 Example 64

N-{4-(1,4-디아제판-1-일)-2-[(페닐술포닐)아미노]페닐]-3,5-디메틸-4-이속사졸술폰아미드 히드로클로라이드 (반응식 3)N- {4- (1,4-diazepane-1-yl) -2-[(phenylsulfonyl) amino] phenyl] -3,5-dimethyl-4-isoxazolesulfonamide hydrochloride (Scheme 3)

화합물을 N-{2-아미노-5-(4-t-부틸옥시카르보닐-1,4-디아제판-1-일)-페닐}벤젠술폰아미드 및 3,5-디메틸이속사졸술포닐클로라이드 (53 mg, 0.269 mmol) 로부터 합성해 32 mg 의 자주색 고체를 수득했다. M+1 506.3 계산치 506.15The compound was converted to N- {2-amino-5- (4-t-butyloxycarbonyl-1,4-diazepane-1-yl) -phenyl} benzenesulfonamide and 3,5-dimethylisoxazolesulfonylchloride Synthesis from (53 mg, 0.269 mmol) gave 32 mg of a purple solid. M + 1 506.3 calc 506.15

Figure 112003042468427-pct00090
Figure 112003042468427-pct00090

실시예 65 Example 65

N-{4-(1,4-디아제판-1-일)-2-[(페닐술포닐)아미노]페닐}-5-플루오로-2-메틸벤젠술폰아미드 히드로클로라이드 (반응식 3)N- {4- (1,4-diazepane-1-yl) -2-[(phenylsulfonyl) amino] phenyl} -5-fluoro-2-methylbenzenesulfonamide hydrochloride (Scheme 3)

화합물을 N-{2-아미노-5-(4-t-부틸옥시카르보닐-1,4-디아제판-1-일)-페닐}벤 젠술폰아미드 및 5-플루오로-2-메틸벤젠술포닐클로라이드 (56 mg, 0.269 mmol) 로부터 합성하여 7 mg 의 자주색 고체를 수득했다. M+1 519.3 계산치 519.15;The compound was treated with N- {2-amino-5- (4-t-butyloxycarbonyl-1,4-diazepane-1-yl) -phenyl} benzensulfonamide and 5-fluoro-2-methylbenzenesulfonate. Synthesis from polyvinylchloride (56 mg, 0.269 mmol) gave 7 mg of a purple solid. M + 1 519.3 calc. 519.15;

Figure 112003042468427-pct00091
Figure 112003042468427-pct00091

실시예 66Example 66

N-{4-(1,4-디아제판-1-일)-2-[(페닐술포닐)아미노]페닐}-4-(메틸술포닐)벤젠술폰아미드 히드로클로라이드 (반응식 3)N- {4- (1,4-diazepane-1-yl) -2-[(phenylsulfonyl) amino] phenyl} -4- (methylsulfonyl) benzenesulfonamide hydrochloride (Scheme 3)

화합물을 N-{2-아미노-5-(4-t-부틸옥시카르보닐-1,4-디아제판-1-일)-페닐}벤젠술폰아미드 및 4-메틸술포닐벤젠술포닐클로라이드 (69 mg, 0.269 mmol) 로부터 합성하여 38 mg 의 자주색 고체를 수득했다. M+1 565.3 계산치 565.12The compound was treated with N- {2-amino-5- (4-t-butyloxycarbonyl-1,4-diazepan-1-yl) -phenyl} benzenesulfonamide and 4-methylsulfonylbenzenesulfonylchloride (69 mg, 0.269 mmol) to give 38 mg of a purple solid. M + 1 565.3 cal 565.12

Figure 112003042468427-pct00092
Figure 112003042468427-pct00092

실시예 67 Example 67

N-{4-(1,4-디아제판-1-일)-2-[(메틸술포닐)아미노]페닐)-N-메틸벤젠술폰아미드 (반응식 3) N- {4- (1,4-diazepane-1-yl) -2-[(methylsulfonyl) amino] phenyl) -N-methylbenzenesulfonamide (Scheme 3)

N-메틸-{2-아미노-5-(4-t-부틸옥시카르보닐-1,4-디아제판-1-일)-페닐}벤젠술폰아미드 (0.196 g, 0.426 mmol) 를 피리딘 (1.67 ml) 에 용해한 후, 메틸 술포닐클로라이드 (57 mg, 0.50 mmol) 을 첨가했다. 반응물을 실온에서 3 시간 동안 교반했다. 혼합물을 농축하고, DCM 중 트리플루오로아세트산 (50%) 으로 30 분 동안 처리한 후, 농축하고, HPLC 분리 전문가에게 의뢰했다. 칼럼 크로마토그래피 DCM/ MeOH (9:1) 에 의한 정제로 32 mg, 0.058 mmol 의 13% 수율로 표제 화합물을 수득했다. N-methyl- {2-amino-5- (4-t-butyloxycarbonyl-1,4-diazepan-1-yl) -phenyl} benzenesulfonamide (0.196 g, 0.426 mmol) was pyridine (1.67 ml) After dissolving in), methyl sulfonylchloride (57 mg, 0.50 mmol) was added. The reaction was stirred at rt for 3 h. The mixture was concentrated, treated with trifluoroacetic acid (50%) in DCM for 30 minutes, then concentrated and referred to an HPLC separation expert. Purification by column chromatography DCM / MeOH (9: 1) gave the title compound in 13% yield of 32 mg, 0.058 mmol.

Figure 112003042468427-pct00093
Figure 112003042468427-pct00093

실시예 68 Example 68

N-{5-(1,4-디아제판-1-일)-2-[메틸(페닐술포닐)아미노]페닐}-4-메틸벤젠술폰아미드 (반응식 3)N- {5- (1,4-diazepane-1-yl) -2- [methyl (phenylsulfonyl) amino] phenyl} -4-methylbenzenesulfonamide (Scheme 3)

N-메틸-{2-아미노-5-(4-t-부틸옥시카르보닐-1,4-디아제판-1-일)-페닐}벤젠술폰아미드 (0.196 g, 0.426 mmol) 를 피리딘 (1.67 ml) 에 용해한 후, p-메틸페닐-술포닐클로라이드 (88 mg, 0.50 mmol) 를 첨가하고, 반응물을 실온에서 3 시간 동안 교반했다. 혼합물을 농축하고, DCM 중의 트리플루오로아세트산 (50%) 으로 30 분 동안 처리한 후, 농축하고, HPLC 분리 전문가에게 의뢰했다. 플래쉬 칼럼 크로마토그래피 DCM/MeOH (9:1) 에 의한 추가 정제로 0.110 g, 0.175 mmol 인 40% 수율의 표제 화합물을 수득했다. N-methyl- {2-amino-5- (4-t-butyloxycarbonyl-1,4-diazepan-1-yl) -phenyl} benzenesulfonamide (0.196 g, 0.426 mmol) was pyridine (1.67 ml) After dissolving in), p-methylphenyl-sulfonylchloride (88 mg, 0.50 mmol) was added and the reaction stirred at room temperature for 3 hours. The mixture was concentrated, treated with trifluoroacetic acid (50%) in DCM for 30 minutes, then concentrated and referred to an HPLC separation expert. Further purification by flash column chromatography DCM / MeOH (9: 1) afforded the title compound in 40% yield of 0.110 g, 0.175 mmol.

Figure 112003042468427-pct00094
Figure 112003042468427-pct00094

모노술폰아미드의 일반적인 제조 방법 General preparation method of monosulfonamide

반응식 4Scheme 4

Figure 112003042468427-pct00095
Figure 112003042468427-pct00095

실시예 69 Example 69

N-[2-아미노-4-(1-피페라지닐)페닐]-3-플루오로벤젠술폰아미드 (반응식 4)N- [2-amino-4- (1-piperazinyl) phenyl] -3-fluorobenzenesulfonamide (Scheme 4)

tert-부틸 4-(3-아미노-4-니트로페닐)-1-피페라진카르복실레이트 (1.5 g, 3.5 mmol) 를 메탄올:THF (4:1) 중에 용해시켰다. 라니-Ni (900 mg) 를 첨가한 후, 히드라진 모노수화물 (900 mg) 을 첨가했다. 반응물을 실온에서 N2 대기 하에 밤새 교반했다. 출발 물질이 존재했다. 라니-Ni (400 mg) 를 첨가하고, 반응물을 밤새 교반했다. 반응물을 셀라이트 패드로 여과한 후, 에탄올로 세척했다. 휘발물을 증발시켜, 93% 의 2-아미노-5-(4-t-부틸카르복실-1-피페라지닐) 아닐린을 수득했다. tert-butyl 4- (3-amino-4-nitrophenyl) -1-piperazinecarboxylate (1.5 g, 3.5 mmol) was dissolved in methanol: THF (4: 1). Raney-Ni (900 mg) was added followed by hydrazine monohydrate (900 mg). The reaction was stirred at rt under N 2 atmosphere overnight. Starting material was present. Raney-Ni (400 mg) was added and the reaction stirred overnight. The reaction was filtered through a pad of celite and washed with ethanol. The volatiles were evaporated to yield 93% of 2-amino-5- (4-t-butylcarboxyl-1-piperazinyl) aniline.

2-아미노-5-(4-t-부틸카르복실-1-피페라지닐)아닐린 (150 mg, 0.382 mmol) 을 CH2Cl2 (2 mL) 에 용해했다. 3-플루오로페닐술포닐클로라이드 (74 mg, 0.382 mmol), 피리딘 (215 ㎕, 2.67 mmol) 을 첨가하고, 반응물을 실온에서 2 시간동안 교반했다. 반응물을 NaHCO3 (포화 수용액) 로 급냉 (quench) 하고, CH2Cl2 로 추출했다. 유기상을 건조 (MgSO4) 시키고, 여과하고 농축하여, 오일 잔사를 수득하 여 플래쉬 칼럼 크로마토그래피 (SiO2, CH3Cl:MeOH:NH3 9:1:0.4%) 로 정제하여, N-[2-아미노-4-(4-tert-부틸카르복실-1-피페라지닐)-3 플루오로벤젠술폰아미드 (80 %) 를 수득했다. 2-amino-5- (4-t-butylcarboxyl-1-piperazinyl) aniline (150 mg, 0.382 mmol) was dissolved in CH 2 Cl 2 (2 mL). 3-fluorophenylsulfonylchloride (74 mg, 0.382 mmol), pyridine (215 μl, 2.67 mmol) was added and the reaction was stirred at rt for 2 h. The reaction was quenched with NaHCO 3 (saturated aqueous solution) and extracted with CH 2 Cl 2 . The organic phase was dried (MgSO 4 ), filtered and concentrated to afford an oil residue which was purified by flash column chromatography (SiO 2 , CH 3 Cl: MeOH: NH 3 9: 1: 0.4%), N- [ 2-amino-4- (4-tert-butylcarboxy-1-piperazinyl) -3 fluorobenzenesulfonamide (80%) was obtained.

N-[2-아미노-4-(4-tert-부틸카르복실-1-피페라지닐)-3-플루오로벤젠술폰아미드 (110 mg) 를 메탄올 (0.5 mL) 중에 용해한 후, 디에틸에테르 (2 mL) 를 첨가했다. 에테르/HCl 기체를 pH = 1 이 될 때까지 첨가했다. 반응물을 실온에서 5 시간 동안 교반하여, 표제 생성물을 백색 고체로서 수득했다. N- [2-amino-4- (4-tert-butylcarboxyl-1-piperazinyl) -3-fluorobenzenesulfonamide (110 mg) was dissolved in methanol (0.5 mL), followed by diethyl ether ( 2 mL) was added. Ether / HCl gas was added until pH = 1. The reaction was stirred at rt for 5 h to afford the title product as a white solid.

Figure 112003042468427-pct00096
Figure 112003042468427-pct00096

실시예 70 Example 70

N-[2-(에틸아미노)-4-(4-메틸-1-피페라지닐)페닐]-3-플루오로벤젠술폰아미드 히드로클로라이드 (반응식 4)N- [2- (ethylamino) -4- (4-methyl-1-piperazinyl) phenyl] -3-fluorobenzenesulfonamide hydrochloride (Scheme 4)

N-2-에틸-4-(4-메틸-1-피페라지닐)-1,2-벤젠디아민 (0.200 g, 0.853 mmol) 및 피리딘 (0.48 mL, 5.97 mmol) 의 DCM (8 mL) 중 용액에 3-플루오로벤젠술포닐 클로라이드 (249 mg, 1.28 mmol) 의 DCM (2 mL) 중 용액을 첨가했다. 혼합물을 실온에서 16 시간 동안 교반했다. DCM (1O mL) 을 첨가하고, 혼합물을 포화 NaHCO3 수용액으로 세척했다. 유기층을 Na2SO4 상에서 건조하고, 여과하고 농축했다. EtOAc/5% MeOH 를 용출액으로 사용하는 Al203 상의 칼럼 크로마토그래피로 두 가지 생성물을 수득했다. 제 1 분획에는 110 mg 의 N-[2-{에틸[(3-플루오로페닐) 술포닐]아미노}-4-(4-메틸-1-피페라지닐)페닐]-3-플루오로벤젠술폰아미드 히드로클로라이드를 함유했다. 제 2 분획에는 100 mg 의 N-[2-에틸아미노)-4-(4-메틸-1-피페라지닐)페닐]-3-플루오로벤젠술폰아미드 히드로클로라이드를 함유했다. 두 생성물이 모두 HCl-염으로 전환되었다. N-[2-(에틸아미노)-4-(4-메틸-1-피페라지닐)페닐]-3-플루오로벤젠술폰아미드 히드로클로라이드: A solution of N-2-ethyl-4- (4-methyl-1-piperazinyl) -1,2-benzenediamine (0.200 g, 0.853 mmol) and pyridine (0.48 mL, 5.97 mmol) in DCM (8 mL) To a solution of 3-fluorobenzenesulfonyl chloride (249 mg, 1.28 mmol) in DCM (2 mL) was added. The mixture was stirred at rt for 16 h. DCM (10 mL) was added and the mixture was washed with saturated aqueous NaHCO 3 solution. The organic layer was dried over Na 2 SO 4 , filtered and concentrated. Column chromatography on Al 2 O 3 using EtOAc / 5% MeOH as eluent gave two products. The first fraction contains 110 mg of N- [2- {ethyl [(3-fluorophenyl) sulfonyl] amino} -4- (4-methyl-1-piperazinyl) phenyl] -3-fluorobenzenesulphone Contains amide hydrochloride. The second fraction contained 100 mg of N- [2-ethylamino) -4- (4-methyl-1-piperazinyl) phenyl] -3-fluorobenzenesulfonamide hydrochloride. Both products were converted to HCl-salts. N- [2- (ethylamino) -4- (4-methyl-1-piperazinyl) phenyl] -3-fluorobenzenesulfonamide hydrochloride:

Figure 112003042468427-pct00097
Figure 112003042468427-pct00097

실시예 71 Example 71

4-클로로-N-[5-(4-메틸-1,4-디아제판-1-일)-2-니트로페닐]벤젠술폰아미드 (반응식 4) 4-chloro-N- [5- (4-methyl-1,4-diazepan-1-yl) -2-nitrophenyl] benzenesulfonamide (Scheme 4)

4-클로로벤젠 술폰아미드 (3.5 g, 18.3 mmol) 를 서서히 수소화나트륨 (1.6 g, 미네랄 오일 중 55% 현탁액, 36.6 mmol) 의 무수 DMF (50 mL) 중의 현탁액에 질소 대기 하에 첨가했다. 혼합물을 40℃ 까지 1 시간 동안 가온하고, 2,4-디플루오로니트로벤젠 (2 mL) 을 적가했다. 상기 혼합물을 60℃ 에서 밤새 교반했다. 냉각된 반응 혼합물을 염산 (1 N, 250 mL) 에 붓고, 에틸 아세테이트 (2 ×50 mL) 으로 추출했다. 유기 추출물을 물로 세척하고, MgSO4 상에서 건조시키고, 증발시켜, 황색 고체를 수득했다. 생성물을 에탄올로부터 재결정했다. 수율 2.4 g (40%). 4-Chlorobenzene sulfonamide (3.5 g, 18.3 mmol) was slowly added to a suspension of anhydrous DMF (50 mL) of sodium hydride (1.6 g, 55% suspension in mineral oil, 36.6 mmol) under a nitrogen atmosphere. The mixture was warmed up to 40 ° C. for 1 hour and 2,4-difluoronitrobenzene (2 mL) was added dropwise. The mixture was stirred at 60 ° C. overnight. The cooled reaction mixture was poured into hydrochloric acid (1 N, 250 mL) and extracted with ethyl acetate (2 x 50 mL). The organic extract was washed with water, dried over MgSO 4 and evaporated to give a yellow solid. The product was recrystallized from ethanol. Yield 2.4 g (40%).

1H NMR (400 MHz, CDCl3) δ6.85 (m,1H), 7.48 (AB, J = 8.3 Hz, 2H), 7.56 (dd, J = 10.01, 2.68 Hz, 1H), 7.94 (AB, J = 8.3 Hz, 2H), 8.21 (dd, J = 9.28, 5.61 Hz, 1H), 10 (bs, 1H). 계산치 N 8.47%, C 43.58%, S 9.70%, H 2.44%; 실측치 N 8.54%, C 43.89%, S 10.00%, H 2.76%. 1 H NMR (400 MHz, CDCl 3 ) δ6.85 (m, 1H), 7.48 (AB, J = 8.3 Hz, 2H), 7.56 (dd, J = 10.01, 2.68 Hz, 1H), 7.94 (AB, J = 8.3 Hz, 2H), 8.21 (dd, J = 9.28, 5.61 Hz, 1H), 10 (bs, 1H). Calc. N 8.47%, C 43.58%, S 9.70%, H 2.44%; Found N 8.54%, C 43.89%, S 10.00%, H 2.76%.

4-클로로-N-[5-플루오로-2-니트로페닐]벤젠술폰아미드 (1 g, 3 mmol) 및 N-메틸호모피페라진 (0.4 mL) 을 함께 130℃ 에서 3 시간 동안 가열했다. 생성물을 냉각시키고, CH2Cl2 (50 mL) 에 용해시키고, 중탄산나트륨 용액으로 세척했다. 유기상을 MgSO4 상에서 건조시키고 증발시켜, 1.05 g 의 황색 고체를 수득해, 톨루엔으로부터 재결정했다. 수율 0.65g (51%)4-chloro-N- [5-fluoro-2-nitrophenyl] benzenesulfonamide (1 g, 3 mmol) and N-methyl homopiperazine (0.4 mL) were heated together at 130 ° C. for 3 hours. The product was cooled down, dissolved in CH 2 Cl 2 (50 mL) and washed with sodium bicarbonate solution. The organic phase was dried over MgSO 4 and evaporated to yield 1.05 g of a yellow solid which was recrystallized from toluene. Yield 0.65 g (51%)

Figure 112003042468427-pct00098
Figure 112003042468427-pct00098

실시예 72 Example 72

N-[2-아미노-5-(1,4-디아제판-1-일)페닐]벤젠술폰아미드 (반응식 4) N- [2-amino-5- (1,4-diazepan-1-yl) phenyl] benzenesulfonamide (Scheme 4)

N-{5-(4-t-부틸옥시카르보닐-1,4-디아제판-1-일)-2-니트로-페닐}벤젠술폰아미드 (1.85 g, 3.88 mmol) 를 EtOH/THF (1:4) 에 용해했다. 히드라진 (0.970 mL, 19.4 mmol) 및 라니-Ni (0.180 g) 를 첨가했다. 실온에서 1 시간 후, 반응물을 젖은 셀라이트로 여과하고, 용매를 제거해 1.71 g 의 무색 오일을 수득했다. Boc-탈보호를, N-{5-(4-t-부틸옥시카르보닐-1,4-디아제판-1-일)-2-아미노-페닐}벤젠술폰아미드 (0.039 g) 를 소량의 MeOH 에 용해하고, HCl/에테르를 첨가하여 수행했다. 혼합물을 실온에서 0.5 시간 동안 정치시키고, 용매를 제거했다. MeOH/에테르로부터 재결정하여 PHA-509592A (23 mg) 를 백색 고체로 수득했다. M+1 347.4 계산치 347.15N- {5- (4-t-butyloxycarbonyl-1,4-diazepan-1-yl) -2-nitro-phenyl} benzenesulfonamide (1.85 g, 3.88 mmol) was added EtOH / THF (1: 4) was dissolved in. Hydrazine (0.970 mL, 19.4 mmol) and Raney-Ni (0.180 g) were added. After 1 hour at room temperature, the reaction was filtered through wet celite and the solvent was removed to yield 1.71 g of a colorless oil. Boc-deprotection, N- {5- (4-t-butyloxycarbonyl-1,4-diazepane-1-yl) -2-amino-phenyl} benzenesulfonamide (0.039 g) Dissolved in and performed by addition of HCl / ether. The mixture was allowed to stand at room temperature for 0.5 hours and the solvent was removed. Recrystallization from MeOH / ether gave PHA-509592A (23 mg) as a white solid. M + 1 347.4 calcd 347.15

Figure 112003042468427-pct00099
Figure 112003042468427-pct00099

실시예 73 Example 73

N-[2-아미노-5-(4-메틸-1,4-디아제판-1-일)페닐]벤젠술폰아미드 히드로클로라이드 (반응식 4) N- [2-amino-5- (4-methyl-1,4-diazepan-1-yl) phenyl] benzenesulfonamide hydrochloride (Scheme 4)

팔라듐 (C 상에서 10%, 0.3 g) 이 있는 메탄올 (50 mL) 중 상기 술폰아미드 (0.6 g, 1.8 mmol) 를 대기압에서 1 시간 동안 140 mL 의 수소를 소비하여 수소화했다. 용액을 여과하고 증발시켜, 무색 오일을 수득했다. 오일을 톨루엔 (20 mL) 중에 용해시켜, 에틸 아세테이트 중의 염화수소 용액으로 처리했다. 생성물을 시클로헥산으로 연화하고, 여과로 수집하여 건조시켰다. 수율 0.44g (73%). 일부를 톨루엔:에탄올 1:1 로부터 재결정했다. The sulfonamide (0.6 g, 1.8 mmol) in methanol (50 mL) with palladium (10% on C, 0.3 g) was hydrogenated by consuming 140 mL of hydrogen for 1 hour at atmospheric pressure. The solution was filtered and evaporated to give a colorless oil. The oil was dissolved in toluene (20 mL) and treated with a solution of hydrogen chloride in ethyl acetate. The product was triturated with cyclohexane, collected by filtration and dried. Yield 0.44 g (73%). Some were recrystallized from toluene: ethanol 1: 1.

Figure 112003042468427-pct00100
Figure 112003042468427-pct00100

실시예 74 Example 74

N-[4-니트로-3-(1-피페라지닐)페닐]벤젠술폰아미드 히드로클로라이드 (반응식 4) N- [4-nitro-3- (1-piperazinyl) phenyl] benzenesulfonamide hydrochloride (Scheme 4)

디플루오로니트로벤젠 (1.31 g, 8.21 mmol), Boc-피페라진 (1.84 g, 9.8 mmol) 및 K2CO3 의 DMF 중 혼합물을 실온에서 밤새 교반했다. 혼합물을 여과하고, DMF 를 제거했다. 잔사를 CH2Cl2 에 용해하고, HCl (1 M) 로 3 회 추출했다. 유기층을 건조 (MgSO4) 시키고, 여과하고 용매를 제거했다. 칼럼 크로마토그래피 (SiO2, CH2Cl2/헵탄, 1:4) 에 의한 정제로 1.14 g 의 황색 고체를 수득했다. A mixture in DMF of difluoronitrobenzene (1.31 g, 8.21 mmol), Boc-piperazine (1.84 g, 9.8 mmol) and K 2 CO 3 was stirred overnight at room temperature. The mixture was filtered and DMF was removed. The residue was dissolved in CH 2 Cl 2 and extracted three times with HCl (1 M). The organic layer was dried (MgSO 4 ), filtered and the solvent removed. Purification by column chromatography (SiO 2 , CH 2 Cl 2 / heptanes, 1: 4) gave 1.14 g of a yellow solid.

1H-NMR δ 7.90 (dd, 1H), 6.77 - 6.69 (m, 2H), 3.60 - 3.57 (m, 4H), 3.03 - 3.00 (m, 4H), 1.46 (s, 9H); MS (posEI-DIP) m/z = 실측치: 348.2 (M+ + Na+). NaH (17.2 mg, 0.43 mmol) 를 4-(2-니트로-5-플루오로페닐)-1-(t-부틸옥시카르보닐)피페라진 (0.079 g, 0.215 mmol) 및 벤젠술폰아미드 (0.044 g, 0.280 mmol) 의 DMF 중 용액에 첨가했다. 혼합물을 80℃ 에서 밤새 가열하고, 여과했다. 칼럼 크로마토그래피 (SiO2, CH2Cl2/헵탄, 1:4) 에 의한 여과로 O.075 g 의 N-[2-니트로-4-(t-부틸옥시카르보닐피페라지닐)]페닐]벤젠술폰아미드를 수득하여, 0.025 mg 를 MeOH 에 용해하고 HCl/에테르를 첨가함으로써 Boc-탈보호를 했다. 혼합물을 0.5 시간 동안 교반한 후, 용매를 제거했다. MeOH/에테르로부터의 재결정으로 24.6 mg 의 황색 고체를 수득했다. 1 H-NMR δ 7.90 (dd, 1H), 6.77-6.69 (m, 2H), 3.60-3.57 (m, 4H), 3.03-3.00 (m, 4H), 1.46 (s, 9H); MS (posEI-DIP) m / z = found: 348.2 (M + + Na + ). NaH (17.2 mg, 0.43 mmol) to 4- (2-nitro-5-fluorophenyl) -1- (t-butyloxycarbonyl) piperazine (0.079 g, 0.215 mmol) and benzenesulfonamide (0.044 g, 0.280 mmol) in DMF. The mixture was heated at 80 ° C. overnight and filtered. Filtration by column chromatography (SiO 2 , CH 2 Cl 2 / heptane, 1: 4) gave 0.15 g of N- [2-nitro-4- (t-butyloxycarbonylpiperazinyl)] phenyl] Benzenesulfonamide was obtained and Boc-deprotected by dissolving 0.025 mg in MeOH and adding HCl / ether. The mixture was stirred for 0.5 h and then the solvent was removed. Recrystallization from MeOH / ether gave 24.6 mg of a yellow solid.

Figure 112003042468427-pct00101
Figure 112003042468427-pct00101

실시예 75 Example 75

N-[4-아미노-3-(1-피페라지닐)페닐]벤젠술폰아미드 히드로클로라이드 (반응식 4) N- [4-amino-3- (1-piperazinyl) phenyl] benzenesulfonamide hydrochloride (Scheme 4)

N-[2-니트로-4-(t-부틸옥시카르보닐피페라지닐)]페닐]벤젠술폰아미드 (50 mg, 0.108 mmol) 의 THF/EtOH 4:1 중 용액에 라니-Ni (5 mg) 및 히드라진 수화물 (27 ㎕, 0.54 mmol) 을 첨가했다. 혼합물을 실온에서 6 시간 동안 교반한 후, 반응 혼합물을 젖은 셀라이트로 여과했다. 용매 제거 및 칼럼 크로마토그래피 (SiO2, CH2Cl2/헵탄/MeOH, 4:5:1) 에 의한 여과로 N-[2-아미노-4-(t-부틸옥시카르보닐-피페라지닐)]페닐]-벤젠술폰아미드를 수득했다. Boc-탈보호를, 화합물을 MeOH 에 용해하고 HCl/에테르를 첨가하여 수행했다. 혼합물을 0.5 시간 동안 교반하고, 용매를 제거했다. 재결정 (MeOH/에테르) 으로 백색 고체를 수득하고, 예비 HPLC 로 정제하여 1O mg 의 최종 생성물을 수득했다. Rani-Ni (5 mg) in a solution in THF / EtOH 4: 1 of N- [2-nitro-4- (t-butyloxycarbonylpiperazinyl)] phenyl] benzenesulfonamide (50 mg, 0.108 mmol) And hydrazine hydrate (27 μl, 0.54 mmol) was added. After the mixture was stirred at room temperature for 6 hours, the reaction mixture was filtered through wet celite. Removal of solvent and filtration by column chromatography (SiO 2 , CH 2 Cl 2 / heptane / MeOH, 4: 5: 1) N- [2-amino-4- (t-butyloxycarbonyl-piperazinyl) ] Phenyl] -benzenesulfonamide was obtained. Boc-deprotection was performed by dissolving the compound in MeOH and adding HCl / ether. The mixture was stirred for 0.5 h and the solvent was removed. Recrystallization (MeOH / ether) gave a white solid which was purified by preparative HPLC to give 10 mg of the final product.

1H-NMR δ7.66 - 7.45 (m, 5H), 6.78 (d, 1H), 6.62 (d, 1H), 6.50 (dd, 1H), 3.39 - 3.35 (m, 4H), 3.02 - 2.99 (m, 4H); MS (posEI-DIP) m/z = 실측치: 333.0 (M+ + H+). 1 H-NMR δ7.66-7.45 (m, 5H), 6.78 (d, 1H), 6.62 (d, 1H), 6.50 (dd, 1H), 3.39-3.35 (m, 4H), 3.02-2.99 (m , 4H); MS (posEI-DIP) m / z = found: 333.0 (M + + H + ).

반응식 5 Scheme 5

Figure 112003042468427-pct00102
Figure 112003042468427-pct00102

방법 5 Method 5

제조된 원액 용액으로부터 취한, CH2Cl2 (2 mL) 중의 4-클로로 3-니트로벤젠술포닐 클로라이드 (1.78 mmol, 1.0 당량) 를, 적당한 Rn 치환 아닐린 (R1-NH2 또는 R1-NH-R3) (1.62 mmol, 1.0 당량) 용액에 피리딘 (11.34 mmol, 7.0 당량) 존재 하에 첨가했다. 4-chloro 3-nitrobenzenesulfonyl chloride (1.78 mmol, 1.0 equiv) in CH 2 Cl 2 (2 mL), taken from the prepared stock solution, was prepared with an appropriate R n substituted aniline (R 1 -NH 2 or R 1- NH-R 3 ) (1.62 mmol, 1.0 equiv) was added to the solution in the presence of pyridine (11.34 mmol, 7.0 equiv).

반응물을 실온에서 밤새 교반했다. 각각의 혼합물을 1N HCl 로 세척한 후, NaHCO3 (포화 수용액) 으로 세척했다. 각각의 유기상을 분리하고, 건조(Na2SO4 )시키고, 여과했다. CH2Cl2 (2 mL) 를 각각의 반응 혼합물에 첨가한 후, K2CO 3 (3.24 mmol, 2.0 당량) 및 호모피페라진 또는 기타 아민 선택물 (예를 들어 R5) (2.11 mmol, 1.3 당량) 을 첨가했다. 각각의 반응 혼합물을 실온에서 2 일 동안 교반했다. 휘발물질을 스피드 백 (speed vac) 을 이용해 제거했다. 각각의 반응혼합물을 4:1 EtOH:THF (25 mL) 에 용해시킨 후, 라니-Ni (EtOH 중 0.5 mL 현탁액) 및 히드라진 모노히드레이트 (8.10 mmol, 5.0 당량) 를 첨가했다. 각각의 혼합물을 실온에서 2 일 동안 교반한 후, 여과했다 (물로 예비처리한 셀라이트 패드). 여 과물을 농축하여 미정제 생성물 (LC-MS) 를 수득했다. 각각의 반응 혼합물의 분취물을 역상 예비 HPLC 로 정제해 분석용 샘플을 수득하여, 그의 HCl 염으로 전환한 후 약학적 시험을 위해 보냈다. The reaction was stirred at rt overnight. Each mixture was washed with 1N HCl and then with NaHCO 3 (saturated aqueous solution). Each organic phase was separated, dried (Na 2 SO 4 ) and filtered. CH 2 Cl 2 (2 mL) was added to each reaction mixture, followed by K 2 CO 3 (3.24 mmol, 2.0 equiv) and homopiperazine or other amine selection (eg R5) (2.11 mmol, 1.3 equiv) ) Was added. Each reaction mixture was stirred at room temperature for 2 days. Volatiles were removed using a speed vac. Each reaction mixture was dissolved in 4: 1 EtOH: THF (25 mL), followed by Raney-Ni (0.5 mL suspension in EtOH) and hydrazine monohydrate (8.10 mmol, 5.0 equiv). Each mixture was stirred at room temperature for 2 days and then filtered (celite pad pretreated with water). The filtrate was concentrated to give crude product (LC-MS). An aliquot of each reaction mixture was purified by reverse phase preparative HPLC to give an analytical sample which was converted to its HCl salt and sent for pharmaceutical testing.

실시예 76 Example 76

3-아미노-4-(1,4-디아제판-1-일)-N-(4-메톡시페닐)벤젠술폰아미드 히드로클로라이드 (반응식 5, 방법 5)3-amino-4- (1,4-diazepane-1-yl) -N- (4-methoxyphenyl) benzenesulfonamide hydrochloride (Scheme 5, method 5)

화합물을 p-아니시딘으로부터 제조했다; (미정제 수득물 0.238 g, 분석용 순수한 샘플의 수득물 0.137 g); Compound was prepared from p-anisidine; (0.238 g of crude yield, 0.137 g of pure sample for analysis);

Figure 112003042468427-pct00103
Figure 112003042468427-pct00103

실시예 77 Example 77

3-아미노-4-(1,4-디아제판-1-일)-N-(3-메톡시페닐)벤젠술폰아미드 히드로클로라이드 (반응식 5, 방법 5)3-amino-4- (1,4-diazepane-1-yl) -N- (3-methoxyphenyl) benzenesulfonamide hydrochloride (Scheme 5, method 5)

화합물을 m-아니시딘으로부터 수득했다; (미정제 수득물 0.546 g, 분석용 순수한 샘플의 수득물 0.020 g); The compound was obtained from m-anisidine; (0.546 g of crude yield, 0.020 g of pure sample for analysis);

Figure 112003042468427-pct00104
Figure 112003042468427-pct00104

실시예 78 Example 78

3-아미노-4-(1,4-디아제판-1-일)-N-(2-메톡시페닐)벤젠술폰아미드 히드로클 로라이드 (반응식 5, 방법 5)3-amino-4- (1,4-diazepane-1-yl) -N- (2-methoxyphenyl) benzenesulfonamide hydrochloride (Scheme 5, method 5)

화합물을 o-아니시딘으로부터 제조했다; (미정제 수득물 0.469 g, 분석용 순수한 샘플의 수득물 0.010 g); Compound was prepared from o-anisidine; (0.469 g of crude yield, 0.010 g of pure sample for analysis);

Figure 112003042468427-pct00105
Figure 112003042468427-pct00105

실시예 79 Example 79

3-아미노-4-(1,4-디아제판-1-일)-N-(3-플루오로페닐)벤젠술폰아미드 히드로클로라이드 (반응식 5, 방법 5)3-amino-4- (1,4-diazepane-1-yl) -N- (3-fluorophenyl) benzenesulfonamide hydrochloride (Scheme 5, method 5)

화합물을 3-플루오로아닐린으로부터 제조했다; (미정제 수득물 0.580 g, 분석용 순수한 샘플의 수득물 0.043 g); Compound was prepared from 3-fluoroaniline; (0.580 g of crude yield, 0.043 g of pure sample for analysis);

Figure 112003042468427-pct00106
Figure 112003042468427-pct00106

실시예 80 Example 80

3-아미노-4-(1,4-디아제판-1-일)-N-메틸-N-페닐벤젠술폰아미드 히드로클로라이드 (반응식 5, 방법 5)3-Amino-4- (1,4-diazepane-1-yl) -N-methyl-N-phenylbenzenesulfonamide hydrochloride (Scheme 5, method 5)

화합물을 N-메틸아닐린으로부터 제조했다; (미정제 수득물 0.590 g, 분석용 순수한 샘플의 수득물 0.010 g); Compound was prepared from N-methylaniline; (0.590 g of crude yield, 0.010 g of pure sample for analysis);

Figure 112003042468427-pct00107
Figure 112003042468427-pct00107

실시예 81 Example 81

3-아미노-4-(1,4-디아제판-1-일)-N-(4-이소프로필페닐)벤젠술폰아미드 히드로클로라이드 (반응식 5, 방법 5)3-amino-4- (1,4-diazepane-1-yl) -N- (4-isopropylphenyl) benzenesulfonamide hydrochloride (Scheme 5, method 5)

화합물을 4-이소프로필아닐린으로부터 제조했다; (미정제 수득물 0.600 g, 분석용 순수한 샘플의 수득물 0.015 g); Compound was prepared from 4-isopropylaniline; (0.600 g of crude yield, 0.015 g of pure sample for analysis);

Figure 112003042468427-pct00108
Figure 112003042468427-pct00108

실시예 82 Example 82

3-아미노-4-(1,4-디아제판-1-일)-N-(4-메틸페닐)벤젠술폰아미드 히드로클로라이드 (반응식 5, 방법 5)3-amino-4- (1,4-diazepane-1-yl) -N- (4-methylphenyl) benzenesulfonamide hydrochloride (Scheme 5, method 5)

화합물을 p-톨루이딘으로부터 제조했다; (미정제 수득물 0.590 g, 분석용 순수한 샘플의 수득물 0.020 g); The compound was prepared from p-toluidine; (0.590 g of crude yield, 0.020 g of pure sample for analysis);

Figure 112003042468427-pct00109
Figure 112003042468427-pct00109

실시예 83 Example 83

3-아미노-4-(1,4-디아제판-1-일)-N-(2,5-디메틸페닐)벤젠술폰아미드 히드로클로라이드 (반응식 5, 방법 5)3-amino-4- (1,4-diazepane-1-yl) -N- (2,5-dimethylphenyl) benzenesulfonamide hydrochloride (Scheme 5, method 5)

화합물을 2,4-디메틸아닐린으로부터 제조했다; (미정제 수득물 0.306 g, 분 석용 순수한 샘플의 수득물 0.015 g); The compound was prepared from 2,4-dimethylaniline; (0.306 g of crude product, 0.015 g of pure sample for analysis);

Figure 112003042468427-pct00110
Figure 112003042468427-pct00110

실시예 84. Example 84.

3-아미노-N-(3-클로로페닐)-4-(1,4-디아제판-1-일)벤젠술폰아미드 히드로클로라이드 (반응식 5, 방법 5)3-amino-N- (3-chlorophenyl) -4- (1,4-diazepane-1-yl) benzenesulfonamide hydrochloride (Scheme 5, method 5)

화합물을 3-클로로아닐린으로부터 제조했다; (미정제 수득물 0.610 g, 분석용 순수한 샘플의 수득물 0.015 g); Compound was prepared from 3-chloroaniline; (0.610 g of crude yield, 0.015 g of pure sample for analysis);

Figure 112003042468427-pct00111
Figure 112003042468427-pct00111

실시예 85 Example 85

3-아미노-4-(1,4-디아제판-1-일)-N-(2-클로로페닐)벤젠술폰아미드 히드로클로라이드 (반응식 5, 방법 5)3-amino-4- (1,4-diazepane-1-yl) -N- (2-chlorophenyl) benzenesulfonamide hydrochloride (Scheme 5, method 5)

화합물을 2-클로로아닐린으로부터 제조했다; (미정제 수득물 0.506 g, 분석용 순수한 샘플의 수득물 0.020 g); Compound was prepared from 2-chloroaniline; (0.506 g of crude yield, 0.020 g of pure sample for analysis);

Figure 112003042468427-pct00112
Figure 112003042468427-pct00112

실시예 86 Example 86

3-아미노-N-(2,4-디클로로페닐)-4-(1,4-디아제판-1-일)벤젠술폰아미드 히드로클로라이드 (반응식 5, 방법 5) 3-amino-N- (2,4-dichlorophenyl) -4- (1,4-diazepane-1-yl) benzenesulfonamide hydrochloride (Scheme 5, method 5)

화합물을 2,4-디클로로아닐린으로부터 제조했다; (미정제 수득물 0.446 g, 분석용 순수한 샘플의 수득물 0.080 g); The compound was prepared from 2,4-dichloroaniline; (0.446 g of crude yield, 0.080 g of pure sample for analysis);

Figure 112003042468427-pct00113
Figure 112003042468427-pct00113

실시예 87 Example 87

3-아미노-N-(2-메틸-5-클로로-페닐)-4-(1,4-디아제판-1-일)벤젠술폰아미드 히드로클로라이드 (반응식 5, 방법 5)3-amino-N- (2-methyl-5-chloro-phenyl) -4- (1,4-diazepane-1-yl) benzenesulfonamide hydrochloride (Scheme 5, method 5)

화합물을 2-메틸-5-클로로아닐린으로부터 제조했다; (미정제 수득물 0.516 g, 분석용 순수한 샘플의 수득물 0.015 g); Compound was prepared from 2-methyl-5-chloroaniline; (0.516 g of crude yield, 0.015 g of pure sample for analysis);

Figure 112003042468427-pct00114
Figure 112003042468427-pct00114

실시예 88 Example 88

3-아미노-N-(2-메틸-3-클로로-페닐)-4-(1,4-디아제판-1-일)벤젠술폰아미드 히드로클로라이드 (반응식 5, 방법 5)3-amino-N- (2-methyl-3-chloro-phenyl) -4- (1,4-diazepane-1-yl) benzenesulfonamide hydrochloride (Scheme 5, method 5)

화합물을 2-메틸-3-클로로아닐린으로부터 제조했디; (미정제 수득물 0.537 g, 분석용 순수한 샘플의 수득물 0.22 g); The compound was prepared from 2-methyl-3-chloroaniline; (0.537 g of crude yield, 0.22 g of pure sample for analysis);

Figure 112003042468427-pct00115
Figure 112003042468427-pct00115

실시예 89 Example 89

3-아미노-N-(4-트리플루오로-페닐)-4-(1,4-디아제판-1-일)벤젠술폰아미드 히 드로클로라이드 (반응식 5, 방법 5) 3-amino-N- (4-trifluoro-phenyl) -4- (1,4-diazepane-1-yl) benzenesulfonamide hydrochloride (Scheme 5, method 5)

화합물을 4-트리플루오로아닐린으로부터 제조했다; (미정제 수득물 0.319 g, 분석용 순수한 샘플의 수득물 0.013 g); Compound was prepared from 4-trifluoroaniline; (0.319 g of crude yield, 0.013 g of pure sample for analysis);

Figure 112003042468427-pct00116
Figure 112003042468427-pct00116

실시예 90 Example 90

3-아미노-N-(4-플루오로페닐)-4-(1,4-디아제판-1-일)벤젠술폰아미드 히드로클로라이드 (반응식 5, 방법 5)3-amino-N- (4-fluorophenyl) -4- (1,4-diazepane-1-yl) benzenesulfonamide hydrochloride (Scheme 5, method 5)

화합물을 4-플루오로아닐린으로부터 제조했다; (미정제 수득물 0.700 g, 분석용 순수한 샘플의 수득물 0.021 g); Compound was prepared from 4-fluoroaniline; (0.700 g of crude yield, 0.021 g of pure sample for analysis);

Figure 112003042468427-pct00117
Figure 112003042468427-pct00117

실시예 91 Example 91

3-아미노-N-(2-플루오로페닐)-4-(1,4디아제판-1-일)벤젠술폰아미드 히드로클로라이드 (반응식 5, 방법 5)3-amino-N- (2-fluorophenyl) -4- (1,4diazepan-1-yl) benzenesulfonamide hydrochloride (Scheme 5, method 5)

화합물을 2-플루오로아닐린으로부터 제조했다; (미정제 수득물 0.646 g, 분석용 순수한 샘플의 수득물 O.O8O g); Compound was prepared from 2-fluoroaniline; (0.646 g of crude yield, O.O8 g of pure sample for analysis);

Figure 112003042468427-pct00118
Figure 112003042468427-pct00118

실시예 93Example 93

4-(1,4-디아제판-1-일)-3-니트로-N-벤젠술폰아미드 히드로클로라이드 (반응식 5, 방법 5) 4- (1,4-diazepane-1-yl) -3-nitro-N-benzenesulfonamide hydrochloride (Scheme 5, method 5)

CH3CN (100 mL) 중 4-클로로-3-니트로-N-벤젠술폰아미드 (1.52 g, 4.87 mmol), K2CO3 (1.01 g, 7.3 mmol) 및 호모피페라진 (0.585 g, 5.8 mmol) 을 70℃ 까지 2 시간 동안 가열했다. 혼합물을 여과하고, 용매를 제거했다. 칼럼 크로마토그래피 (CH2Cl2/MeOH/헵탄 4:1:5 ×0.2 % NH3) 에 의해 1.34 g 의 4-(1,4-디아제판-1-일)-3-니트로-N-벤젠술폰아미드를 0.152 g 의 디알킬화 생성물과 함께 수득했다. 생성물 (0.040 g) 을 그의 HCl-염으로 전환시켜, 0.038 g 의 최종 생성물을 수득했다. 분석치 (C17H21ClN404S ×0.5H2O) C, H, N.; MS (posESI) m/z = 377.4 (M + H+). 4-Chloro-3-nitro-N-benzenesulfonamide (1.52 g, 4.87 mmol), K 2 CO 3 (1.01 g, 7.3 mmol) and homopiperazine (0.585 g, 5.8 mmol) in CH 3 CN (100 mL) ) Was heated to 70 ° C. for 2 hours. The mixture was filtered and the solvent removed. 1.34 g of 4- (1,4-diazepane-1-yl) -3-nitro-N-benzene by column chromatography (CH 2 Cl 2 / MeOH / heptane 4: 1: 5 × 0.2% NH 3 ) Sulfonamide was obtained with 0.152 g of dialkylation product. The product (0.040 g) was converted into its HCl-salt to yield 0.038 g of the final product. Anal (C 17 H 21 ClN 4 0 4 S × 0.5H 2 O) C, H, N .; MS (posESI) m / z = 377.4 (M + H + ).

실시예 94 Example 94

3-아미노-4-(1,4-디아제판-1-일)-N-페닐벤젠술폰아미드 히드로클로라이드 (반응식 5, 방법 5)3-amino-4- (1,4-diazepane-1-yl) -N-phenylbenzenesulfonamide hydrochloride (Scheme 5, method 5)

4-(1,4-디아제판-1-일)-3-니트로-N-페닐벤젠술폰아미드 (0.599 g, 1.6 mmol) 를 EtOH/THF (1:4) 중에 용해시켰다. 히드라진 (0.398 mL, 8.0 mmol) 및 라니-Ni (0.060 g) 를 첨가했다. 실온에서 1 시간 후, 반응물을 젖은 셀라이트로 여과하고, 용매를 제거했다. 생성물을 MeOH 에 용해시켜 HCl/에테르를 첨가해 그의 HCl 염으로 전환했다. 용매를 제거하고 MeOH/에테르로부터 재결정하여 0.537 g 의 백색 고체를 수득했다. 분석치. (C17H21ClN404S ×1.5H20) C, H, N.; MS (posESI) m/z = 347.4 (M+H+). 4- (1,4-diazepane-1-yl) -3-nitro-N-phenylbenzenesulfonamide (0.599 g, 1.6 mmol) was dissolved in EtOH / THF (1: 4). Hydrazine (0.398 mL, 8.0 mmol) and Raney-Ni (0.060 g) were added. After 1 hour at room temperature, the reaction was filtered through wet celite and the solvent was removed. The product was dissolved in MeOH and converted to its HCl salt by the addition of HCl / ether. The solvent was removed and recrystallized from MeOH / ether to yield 0.537 g of a white solid. Analysis value. (C 17 H 21 ClN 4 0 4 S × 1.5H 2 0) C, H, N .; MS (posESI) m / z = 347.4 (M + H + ).

실시예 92 Example 92

3-아미노-4-(4-메틸-1,4-디아제판-1-일)-N-페닐벤젠술폰아미드 (반응식 5, 방법 5) 3-amino-4- (4-methyl-1,4-diazepan-1-yl) -N-phenylbenzenesulfonamide (Scheme 5, method 5)

4-클로로-3-니트로벤젠술포닐 클로라이드 (460 mg, 1.8 mmol) 를, 아닐린 (25 0 mg, 2.7 mmol) 의 CH2Cl2 (10 mL) 중 무색 용액에 첨가한 후, 피리딘 (O.8O mL, 10.0 mmol) 을 첨가했다. 생성된 오렌지색 용액을 실온에서 30 분 동안 교반한 후, 혼합물을 진공 하에 농축했다. 2M 수성 HCl 로 산성화한 후, EtOAc 를 사용해 추출한 후, Na2SO4 로 건조시킨 후, 실리카의 플러그로 여과하여, 500 mg (62%) 의 4-클로로-3-니트로-N-페닐벤젠술폰아미드를 수득했다. 4-Chloro-3-nitrobenzenesulfonyl chloride (460 mg, 1.8 mmol) was added to a colorless solution of aniline (25 0 mg, 2.7 mmol) in CH 2 Cl 2 (10 mL), followed by pyridine (O. 80 mL, 10.0 mmol) was added. The resulting orange solution was stirred at room temperature for 30 minutes, then the mixture was concentrated in vacuo. Acidified with 2M aqueous HCl, extracted with EtOAc, dried over Na 2 SO 4 , filtered with a plug of silica, and 500 mg (62%) of 4-chloro-3-nitro-N-phenylbenzenesulphone An amide was obtained.

Figure 112003042468427-pct00119
Figure 112003042468427-pct00119

MS(negESI) m/z = 311 (M - H+). 1-메틸호모피페라진 (258 mg, 2.3 mmol) 을, 상기 수득한 CH2Cl2 (20 mL) 중 4-클로로-3-니트로-N-페닐벤젠술폰아미드 (500 mg, 1.6 mmol) 의 용액에 첨가한 후, K2CO3 (310 mg, 2.3 mmol) 을 첨가했다. 반응 혼합물을 환류로 가열했다. 2.5 시간 후, 용액을 진공 하에 농축했다. pH = 6 로 조정한 후, 생성물을 EtOAc 을 사용해 추출한 후, Na2SO4 로 건조시키고 농축 하여, 450 mg (72%) 의 4-(4-메틸-1,4-디아제판-1-일)-3-N-니트로-N-페닐벤젠술폰아미드를 오렌지색 오일로 수득했다.MS (negESI) m / z = 311 (M−H + ). A solution of 1-methylhomopiperazine (258 mg, 2.3 mmol) in 4-chloro-3-nitro-N-phenylbenzenesulfonamide (500 mg, 1.6 mmol) in CH 2 Cl 2 (20 mL) obtained above. After addition to, K 2 CO 3 (310 mg, 2.3 mmol) was added. The reaction mixture was heated to reflux. After 2.5 hours, the solution was concentrated in vacuo. After adjusting to pH = 6, the product was extracted with EtOAc, then dried over Na 2 SO 4 and concentrated to 450 mg (72%) of 4- (4-methyl-1,4-diazepan-1-yl ) -3-N-nitro-N-phenylbenzenesulfonamide was obtained as an orange oil.

1H NMR (CDCl3) δ8.15 (d, 1H), 7.60 (dd, 1H), 7.15 (mn), 6.95 (d, 1H), 3.45 (m, 2H), 3.30 (m, 2H), 2.75 (m, 2H), 2.60 (m, 2H), 2.35 (s, 3H), 1.95 (m, 2H). MS (posESI) m/z = 391(M + H+). 1 H NMR (CDCl 3 ) δ8.15 (d, 1H), 7.60 (dd, 1H), 7.15 (mn), 6.95 (d, 1H), 3.45 (m, 2H), 3.30 (m, 2H), 2.75 (m, 2H), 2.60 (m, 2H), 2.35 (s, 3H), 1.95 (m, 2H). MS (posESI) m / z = 391 (M + H + ).

라니-Ni (EtOH 중 슬러리) 로 활성화된 EtOH/THF (4/1, 25 mL) 중 4-(4-메틸-1,4-디아제판-1-일)-3-니트로-N-페닐벤젠술폰아미드 (225 mg, 0.58 mmol) 용액에 히드라진 모노수화물 (142 ㎕, 2.9 mmol) 를 첨가했다. 30 분 동안 실온에서 교반한 후, 혼합물을 여과하고 황색 용액을 농축하여 황색 오일을 수득했다. 오일을 디에틸 에테르/EtOAc 혼합물에 용해한 후, 과량의 HCl/에테르를 첨가했다. 생성된 침전을 여과하고, 에테르로 세척한 후, 진공 하에 40℃ 에서 건조하여 88 mg (38%) 의 3-아미노-4-(4-메틸-1,4-디아제판-1-일)-N-페닐벤젠술폰아미드를 베이지색 고체로서 수득했다. Mp 84 - 85℃. MS (posESI) m/z = 361 (M + H+). 4- (4-methyl-1,4-diazepan-1-yl) -3-nitro-N-phenylbenzene in EtOH / THF (4/1, 25 mL) activated with Raney-Ni (slurry in EtOH) To a solution of sulfonamide (225 mg, 0.58 mmol) was added hydrazine monohydrate (142 μl, 2.9 mmol). After stirring for 30 minutes at room temperature, the mixture was filtered and the yellow solution was concentrated to give a yellow oil. The oil was dissolved in a diethyl ether / EtOAc mixture, then excess HCl / ether was added. The resulting precipitate was filtered off, washed with ether and dried at 40 ° C. in vacuo to give 88 mg (38%) of 3-amino-4- (4-methyl-1,4-diazepan-1-yl)- N-phenylbenzenesulfonamide was obtained as a beige solid. Mp 84-85 ° C. MS (posESI) m / z = 361 (M + H + ).

Figure 112003042468427-pct00120
Figure 112003042468427-pct00120

실시예 98 Example 98

3-아미노-N-(3-클로로페닐)-4-(4-메틸-1-1-피페라지닐)벤젠술폰아미드 히드로클로라이드 (반응식 5, 방법 5)3-amino-N- (3-chlorophenyl) -4- (4-methyl-1-1-piperazinyl) benzenesulfonamide hydrochloride (Scheme 5, method 5)

CH2Cl2 (2 mL) 중의 4-클로로-3-니트로벤젠술포닐클로라이드 (1 g, 3.9 mmol), 3-클로로아닐린 (0.5 mL, 4.7 mmol) 및 피리딘 (1.6 mL) 의 혼합물을 실온에서 교반했다. 반응물을 NaHCO3 (포화 수용액, 30 mL ×3) 으로 급냉했다. 유기상을 분리하고, 건조 (MgSO4) 시키고, 여과했다. 휘발물질을 증발시키고, 잔자를 칼럼 크로마토그래피 (SiO2, 펜탄:EtOAc, 4:1) 로 정제하여 4-클로로-N-(3-클로로페닐)-3-니트로벤젠술폰아미드를 수득했다; MS (posESI) m/z = 349.2 (M + H+). A mixture of 4-chloro-3-nitrobenzenesulfonylchloride (1 g, 3.9 mmol), 3-chloroaniline (0.5 mL, 4.7 mmol) and pyridine (1.6 mL) in CH 2 Cl 2 (2 mL) at room temperature Stirred. The reaction was quenched with NaHCO 3 (saturated aqueous solution, 30 mL × 3). The organic phase was separated, dried (MgSO 4 ) and filtered. The volatiles were evaporated and the residue was purified by column chromatography (SiO 2 , pentane: EtOAc, 4: 1) to give 4-chloro-N- (3-chlorophenyl) -3-nitrobenzenesulfonamide; MS (posESI) m / z = 349.2 (M + H + ).

Figure 112003042468427-pct00121
Figure 112003042468427-pct00121

여과물인 CH3CN (2.5 mL) 중의 4-클로로-N-(3-클로로페닐)-3-니트로벤젠술폰아미드 (0.45 g, 1.3 mmol), N-메틸피페라진 (0.191 mL, 1.73 mmol) 및 K2CO3 (359 mg, 2.6 mmol) 를 농축하여 잔사를 수득해 칼럼 크로마토그래피 (SiO2, CHCl3:MeOH: NH3 9:1:0.4 %) 로 정제하여 420 mg 의 N-(3-클로로페닐)-4-(4-메틸- 1-피페라지닐)-3-니트로벤젠술폰아미드 (85 %) 를 수득했다. HPLC 분석에 의한 순도 >95 %. 화합물을 THF (1 mL) 에 용해시키고 에탄올 (5 mL) 을 첨가했다. 용액을 라니-Ni (50 mg) 및 히드라진 모노수화물 (0.05 mL) 로 밤새 처리했다. 라니-Ni 를 여과 (셀라이트 패드) 하고, 휘발 물질을 증발시켜, 잔사를 칼럼 크로마토그래피 (SiO2, CHCl3:MeOH:NH3 9:1:0.4 %) 로 정제했다. 생성물을 디에틸 에테르 중에서 HCl 기체로 처리해 히드로클로라이드염으로 분리하여 170 mg 의 최종 생성물을 수득했다. (32 %). 4-chloro-N- (3-chlorophenyl) -3-nitrobenzenesulfonamide (0.45 g, 1.3 mmol), N-methylpiperazine (0.191 mL, 1.73 mmol) in filtrate CH 3 CN (2.5 mL) and K 2 CO 3 (359 mg, 2.6 mmol) was concentrated to give a residue, which was purified by column chromatography (SiO 2 , CHCl 3 : MeOH: NH 3 9: 1: 0.4%) to give 420 mg of N- (3- Chlorophenyl) -4- (4-methyl-1-piperazinyl) -3-nitrobenzenesulfonamide (85%) was obtained. Purity> 95% by HPLC analysis. The compound was dissolved in THF (1 mL) and ethanol (5 mL) was added. The solution was treated with Raney-Ni (50 mg) and hydrazine monohydrate (0.05 mL) overnight. Raney-Ni was filtered (celite pad), the volatiles were evaporated, and the residue was purified by column chromatography (SiO 2 , CHCl 3 : MeOH: NH 3 9: 1: 0.4%). The product was treated with HCl gas in diethyl ether to separate the hydrochloride salt to give 170 mg of the final product. (32%).

Figure 112003042468427-pct00122
Figure 112003042468427-pct00122

실시예 99 Example 99

3-아미노-N-(2-메톡시페닐)-4-(4-메틸-1-피페라지닐)벤젠술폰아미드 히드로클로라이드 (반응식 5, 방법 5) 3-amino-N- (2-methoxyphenyl) -4- (4-methyl-1-piperazinyl) benzenesulfonamide hydrochloride (Scheme 5, method 5)

화합물을 CH2Cl2 (2 mL) 중의 4-클로로-3-니트로벤젠술포닐클로라이드 (1g, 3.9 mmol), 2-메톡시아닐린 (0.53 mL, 4.7 mmol) 및 피리딘 (1.6 mL) 으로부터 제조했다. 4-클로로-N-(2-메톡시페닐)-3-니트로벤젠술폰아미드 (0.345 mg) 를 N-메틸피페라진 (0.144 mL) 과 반응시켜 N-(2-메톡시페닐)-4-(4-메틸-1-피페라지닐)-3-니트로벤젠술폰아미드를 수득해, 라니-Ni 및 히드라진 모노수화물로 처리했다. 최종 생성물은 그의 HCl 염으로서 분리했다.The compound was prepared from 4-chloro-3-nitrobenzenesulfonylchloride (1 g, 3.9 mmol), 2-methoxyaniline (0.53 mL, 4.7 mmol) and pyridine (1.6 mL) in CH 2 Cl 2 (2 mL). . 4-Chloro-N- (2-methoxyphenyl) -3-nitrobenzenesulfonamide (0.345 mg) was reacted with N-methylpiperazine (0.144 mL) to give N- (2-methoxyphenyl) -4- ( 4-Methyl-1-piperazinyl) -3-nitrobenzenesulfonamide was obtained and treated with Raney-Ni and hydrazine monohydrate. The final product was isolated as its HCl salt.

Figure 112003042468427-pct00123
Figure 112003042468427-pct00123

실시예 100 Example 100

3-아미노-N-(2-메톡시페닐)-4-(1-피페라지닐)벤젠술폰아미드 히드로클로라이드 (반응식 5, 방법 5) 3-amino-N- (2-methoxyphenyl) -4- (1-piperazinyl) benzenesulfonamide hydrochloride (Scheme 5, method 5)

화합물을 CH2Cl2 (2 mL) 중의 4-클로로-3-니트로벤젠술포닐 클로라이드 (1 g, 3.9 mmol), 2-메톡시아닐린 (0.53 mL, 4.7 mmol) 및 피리딘 (1.6 mL) 으로부터 제조했다. 4-클로로-N-(2-메톡시페닐)-3-니트로벤젠술폰아미드 (0.345 g) 를 피페라진 (O.111 g) 과 반응시켜 N-(2-메톡시페닐)-4-(피페라지닐)-3-니트로벤젠술폰아미드를 수득했다. 이를 라니-Ni 및 히드라진 모노수화물로 처리했다. 최종 생성물은 그의 HCl 염으로 분리했다. The compound is prepared from 4-chloro-3-nitrobenzenesulfonyl chloride (1 g, 3.9 mmol), 2-methoxyaniline (0.53 mL, 4.7 mmol) and pyridine (1.6 mL) in CH 2 Cl 2 (2 mL). did. 4-chloro-N- (2-methoxyphenyl) -3-nitrobenzenesulfonamide (0.345 g) was reacted with piperazine (O.111 g) to yield N- (2-methoxyphenyl) -4- (pi Ferrazinyl) -3-nitrobenzenesulfonamide was obtained. This was treated with Raney-Ni and hydrazine monohydrate. The final product was separated by its HCl salt.

Figure 112003042468427-pct00124
Figure 112003042468427-pct00124

실시예 95 Example 95

2-(1,4-디아제판-1-일)-5-(4-모르폴리닐술포닐)아닐린 히드로클로라이드 (반응식 5, 방법 5)2- (1,4-diazepane-1-yl) -5- (4-morpholinylsulfonyl) aniline hydrochloride (Scheme 5, method 5)

CH3CN (1O mL) 중 호모피페라진 (O.196 g, 1.95 mmol), 4-[(4-클로로-3-니트로페닐)술포닐]모르폴린 (0.461 g, 1.50 mmol) 및 K2CO3 (0.415 g, 3.00 mmol) 을 65℃ 에서 16 시간 동안 교반했다. CH2Cl2 (1O mL) 를 첨가하고, 혼합물을 여과하고 농축했다. 미정제 생성물을 CHCl3 → CHCl3/10% MeOH + 0.4% 암모니아수를 사용하여 실리카 상에서 칼럼 크로마토그래피로 정제하여, 0.546 g 의 생성물을 황색 고체로 수득했다(수율 98%):Homopiperazine (O.196 g, 1.95 mmol), 4-[(4-chloro-3-nitrophenyl) sulfonyl] morpholine (0.461 g, 1.50 mmol) and K 2 CO in CH 3 CN (10 mL) 3 (0.415 g, 3.00 mmol) was stirred at 65 ° C. for 16 h. CH 2 Cl 2 (10 mL) was added and the mixture was filtered and concentrated. The crude product was purified by column chromatography on silica using CHCl 3 → CHCl 3 /10% MeOH + 0.4% ammonia water to give 0.546 g of the product as a yellow solid (yield 98%):

Figure 112003042468427-pct00125
Figure 112003042468427-pct00125

30 mL 의 4:1 EtOH:THF 용매계 중의 1-[4-(4-모르폴리닐술포닐)-2-니트로페 닐]-1,4-디아제판 (0.445 g, 1.20 mmol) 용액에 라니-Ni (EtOH 중 현탁액 100 mg) 을 첨가하고, 히드라진 모노수화물 (300 mg, 6.00 mmol) 을 첨가했다. 혼합물을 세게 4 시간 동안 교반한 후, 물로 예비처리된 셀라이트로 여과했다. 여과물을 농축한 후, CH3CN 에 재용해시키고, 다시 농축하고 최종적으로 톨루엔을 첨가하고, 1 회 더 혼합물을 농축해 갈색 고체를 수득했다. 미정제 생성물을 칼럼 크로마토그래피 (SiO2, CHCl3/MeOH/NH3 9:1:0.4%) 로 정제하여 0.365 g (수율 89%) 의 순수한 생성물을 고체로서 수득했다. 유리된 염기를 그의 HCl 염으로 전환시켰다:Raney- in a solution of 1- [4- (4-morpholinylsulfonyl) -2-nitropenyl] -1,4-diazepane (0.445 g, 1.20 mmol) in 30 mL of a 4: 1 EtOH: THF solvent system. Ni (100 mg of suspension in EtOH) was added and hydrazine monohydrate (300 mg, 6.00 mmol) was added. The mixture was stirred vigorously for 4 hours and then filtered through celite pretreated with water. The filtrate was concentrated, then redissolved in CH 3 CN, concentrated again and finally toluene was added and the mixture was concentrated once more to give a brown solid. The crude product was purified by column chromatography (SiO 2 , CHCl 3 / MeOH / NH 3 9: 1: 0.4%) to give 0.365 g (89% yield) of the pure product as a solid. The free base was converted to its HCl salt:

Figure 112003042468427-pct00126
Figure 112003042468427-pct00126

중간체 17 Intermediate 17

4-클로로-N-(2-메톡시-페닐)-3-니트로벤젠술폰아미드 (반응식 5, 방법 5) 4-Chloro-N- (2-methoxy-phenyl) -3-nitrobenzenesulfonamide (Scheme 5, Method 5)

4-클로로-3-니트로벤젠술폰아미드 (1.73 g, 6.78 mmol) 를 CH2Cl2 (7.0 mL) 에 용해했다. o-아니시딘 (1.00 g, 8.13 mmol) 을 실온에서 적가한 후, 피리딘 (2.0 mL) 을 서서히 첨가했다. 교반을 16 시간 연속한 후, 반응 혼합물을 EtOAc (50 mL) 로 희석하고 1 M HCl (3 × 50 mL) 로 세척했다. 유기상을 건조 (MgSO4) 시키고 여과하고 증발시켜 갈색 고체를 수득하여, 에탄올/물로부터 재결정하여, 2.22 g (95%) 의 생성물을 백색 결정으로 수득했다. 4-chloro-3-nitrobenzenesulfonamide (1.73 g, 6.78 mmol) was dissolved in CH 2 Cl 2 (7.0 mL). o-anisidine (1.00 g, 8.13 mmol) was added dropwise at room temperature, and then pyridine (2.0 mL) was added slowly. After stirring was continued for 16 hours, the reaction mixture was diluted with EtOAc (50 mL) and washed with 1 M HCl (3 × 50 mL). The organic phase was dried (MgSO 4 ), filtered and evaporated to give a brown solid which was recrystallized from ethanol / water to give 2.22 g (95%) of the product as white crystals.

Figure 112003042468427-pct00127
Figure 112003042468427-pct00127

술폰아미드 양성자가 관찰되지 않았다. No sulfonamide protons were observed.

중간체 18 Intermediate 18

4-클로로-3-니트로-N-페닐-벤젠술폰아미드 (반응식 5, 방법 5) 4-Chloro-3-nitro-N-phenyl-benzenesulfonamide (Scheme 5, Method 5)

반응 플라스크에서 2 부의 4-클로로-3-니트로벤젠술폰아미드 (1.73 g, 6.78 mmol) 를 CH2Cl2 (7.0 mL) 에 용해했다. 아닐린 (757 mg, 8.13 mmol) 을 실온에서 적가한 후, 피리딘 (2.0 mL) 을 서서히 첨가했다. 16 시간 연속 교반 후, 반응 혼합물을 에틸 아세테이트 (50 mL) 로 희석하고, 1 M HCl (3 ×5O mL) 로 세척했다. 유기상을 건조 (MgSO4) 시키고 증발시켜, 갈색 고체를 수득하고, 에탄올/물로부터 재결정하여 백색 고체 2.04 g (96%) 를 생성물로서 수득했다:Two parts of 4-chloro-3-nitrobenzenesulfonamide (1.73 g, 6.78 mmol) were dissolved in CH 2 Cl 2 (7.0 mL) in the reaction flask. Aniline (757 mg, 8.13 mmol) was added dropwise at room temperature, and then pyridine (2.0 mL) was added slowly. After 16 h of continuous stirring, the reaction mixture was diluted with ethyl acetate (50 mL) and washed with 1 M HCl (3 × 50 mL). The organic phase was dried (MgSO 4 ) and evaporated to give a brown solid and recrystallized from ethanol / water to give 2.04 g (96%) of a white solid as product:

Figure 112003042468427-pct00128
Figure 112003042468427-pct00128

4-클로로 니트로-N-아릴-벤젠술폰아미드와 아민 (R4-chloro nitro-N-aryl-benzenesulfonamide and amine (R 55 ) 사이의 반응에 대한 일반적인 과정 (반응식 5, 방법 5) General process for reactions between (Scheme 5, Method 5)

중간체 17 (343 mg, 1.00 mmol) 및 중간체 12 (313 mg, 1.00 mmol) 의 CH3CN (5 mL) 중 용액을 K2CO3 (276 mg, 2.00 mmol) 및 아민 (R5) (1.30 mmol) 으로 처리하고 80℃ 에서 16 시간 동안 가열했다. 반응 혼합물을 에틸 아세테이트 (50 mL) 로 희석하고, 포화 Na2CO3 (3 ×5O mL) 로 세척하고, 건조 (Na2SO4 ) 한 후 증발시켜, 정제하지 않고 후속 단계에 사용될 수 있는 생성물을 수득했다.A solution of intermediate 17 (343 mg, 1.00 mmol) and intermediate 12 (313 mg, 1.00 mmol) in CH 3 CN (5 mL) was charged with K 2 CO 3 (276 mg, 2.00 mmol) and amine (R 5 ) (1.30 mmol). ) And heated at 80 ° C. for 16 h. The reaction mixture is diluted with ethyl acetate (50 mL), washed with saturated Na 2 CO 3 (3 × 50 mL), dried (Na 2 SO 4 ) and evaporated to the next step which can be used without purification without purification. Obtained.

중간체 19 Intermediate 19

N-(2-메톡시페닐)-4-(3-메틸-피페라진-1-일)-3-니트로벤젠술폰아미드 (반응식 5, 방법 5)N- (2-methoxyphenyl) -4- (3-methyl-piperazin-1-yl) -3-nitrobenzenesulfonamide (Scheme 5, method 5)

중간체 17 (343 mg, 1.00 mmol) 및 K2CO3 (276 mg, 2.00 mmol) 의 CH3CN (5 mL) 중 용액을 2-메틸피페라진 (130 mg, 1.30 mmol) 로 처리했다. 80℃ 에서의 16 시간 교반 후, 반응 혼합물을 EtOAc (50 mL) 로 희석하여 포화 Na2CO3 (aq) (3 ×5O mL) 로 세척했다. 유기상을 건조 (Na2SO4) 하고, 증발시켜 398 mg 의 황색 발포체로서 표제 화합물 (98%) 을 수득했다. A solution of intermediate 17 (343 mg, 1.00 mmol) and K 2 CO 3 (276 mg, 2.00 mmol) in CH 3 CN (5 mL) was treated with 2-methylpiperazine (130 mg, 1.30 mmol). After 16 h stirring at 80 ° C., the reaction mixture was diluted with EtOAc (50 mL) and washed with saturated Na 2 CO 3 (aq) (3 × 50 mL). The organic phase was dried (Na 2 SO 4 ) and evaporated to afford the title compound (98%) as 398 mg of yellow foam.

Figure 112003042468427-pct00129
Figure 112003042468427-pct00129

술폰아미드 및 아민 양성자가 관찰되지 않았다. No sulfonamide and amine protons were observed.

중간체 20 Intermediate 20

4-(헥사히드로-피롤로[1,2-a]피라진-2-일)-N-(2-메톡시페닐)-3-니트로벤젠술폰아미드 (반응식 5, 방법 5)4- (hexahydro-pyrrolo [1,2-a] pyrazin-2-yl) -N- (2-methoxyphenyl) -3-nitrobenzenesulfonamide (Scheme 5, method 5)

중간체 17 (343 mg, 1.00 mmol) 및 K2CO3 (276 mg, 2.00 mmol) 의 CH3CN (5 mL) 중 용액을 옥타히드로피롤로[1,2-a]피라진 (164 mg, 1.30 mmol) 으로 처리했다. 80℃ 에서의 16 시간 동안 교반 후, 반응 혼합물을 EtOAc (50 mL) 로 희석하 고, 포화 Na2CO3 (3 ×50 mL) 로 세척했다. 유기층을 건조 (Na2SO4 ) 시키고, 증발시켜 407 mg 의 황색 발포체인 표제 화합물 (94%) 을 수득했다.A solution of intermediate 17 (343 mg, 1.00 mmol) and K 2 CO 3 (276 mg, 2.00 mmol) in CH 3 CN (5 mL) was converted to octahydropyrrolo [1,2-a] pyrazine (164 mg, 1.30 mmol). ). After stirring for 16 h at 80 ° C., the reaction mixture was diluted with EtOAc (50 mL) and washed with saturated Na 2 CO 3 (3 × 50 mL). The organic layer was dried (Na 2 SO 4 ) and evaporated to afford 407 mg of the title compound (94%) as a yellow foam.

Figure 112003042468427-pct00130
Figure 112003042468427-pct00130

술폰아미드 및 아민 양성자가 관찰되지 않았다. No sulfonamide and amine protons were observed.

중간체 21 Intermediate 21

3-니트로-N-페닐-4-피페라진-1-일-벤젠술폰아미드 (반응식 5, 방법 5) 3-nitro-N-phenyl-4-piperazin-1-yl-benzenesulfonamide (Scheme 5, method 5)

화합물을 중간체 18 및 피페라진으로부터 제조해 362 mg 의 밝은 오렌지색 고체 (100%) 를 수득했다:The compound was prepared from intermediate 18 and piperazine to give 362 mg of a light orange solid (100%):

Figure 112003042468427-pct00131
Figure 112003042468427-pct00131

중간체 22 Intermediate 22

4-(3-메틸-피페라진-1-일)-3-니트로-N-페닐-벤젠술폰아미드 (반응식 5, 방법 5) 4- (3-Methyl-piperazin-1-yl) -3-nitro-N-phenyl-benzenesulfonamide (Scheme 5, method 5)

화합물을 중간체 18 및 1-메틸피페라진으로부터 제조해 373 mg 의 오렌지-갈색 고체를 수득했다 (99%):The compound was prepared from intermediate 18 and 1-methylpiperazine to give 373 mg of orange-brown solid (99%):

Figure 112003042468427-pct00132
Figure 112003042468427-pct00132

중간체 23 Intermediate 23                 

4-(4-에틸-피페라진-1-일)-3-니트로-N-페닐-벤젠술폰아미드 (반응식 5, 방법 5) 4- (4-Ethyl-piperazin-1-yl) -3-nitro-N-phenyl-benzenesulfonamide (Scheme 5, method 5)

화합물을 중간체 18 및 1-에틸피페라진으로부터 제조해 386 mg 의 오렌지색 발포체를 수득했다 (99%): The compound was prepared from intermediate 18 and 1-ethylpiperazine to give 386 mg of orange foam (99%):

Figure 112003042468427-pct00133
Figure 112003042468427-pct00133

중간체 24 Intermediate 24

4-(헥사히드로피롤로[1,2-a]피라진-2-일)-3-니트로-N-페닐-벤젠술폰아미드 (반응식 5, 방법 5) 4- (hexahydropyrrolo [1,2-a] pyrazin-2-yl) -3-nitro-N-phenyl-benzenesulfonamide (Scheme 5, method 5)

화합물을 중간체 18 및 헥사히드로피롤로[1,2-a]2-피라진으로부터 제조해 372 mg 의 오렌지색 발포체를 수득했다 (92%):The compound was prepared from intermediate 18 and hexahydropyrrolo [1,2-a] 2-pyrazine to give 372 mg of orange foam (92%):

Figure 112003042468427-pct00134
Figure 112003042468427-pct00134

중간체 25 Intermediate 25

4-(5-메틸-2,5-디아자-비시클로[2.2.1]헵틸-2-일)-3-니트로-N-페닐-벤젠술폰아미드 (반응식 5, 방법 5)4- (5-Methyl-2,5-diaza-bicyclo [2.2.1] heptyl-2-yl) -3-nitro-N-phenyl-benzenesulfonamide (Scheme 5, method 5)

화합물을 중간체 18 및 5-메틸-2,5-디아자-비시클로[2.2.1]2-헵탄으로부터 제조해 374 mg 의 황색 고체를 수득했다 (96%): The compound was prepared from intermediate 18 and 5-methyl-2,5-diaza-bicyclo [2.2.1] 2-heptane to give 374 mg of a yellow solid (96%):

Figure 112003042468427-pct00135
Figure 112003042468427-pct00135

중간체 26 Intermediate 26

4-(트란스-2,5-디메틸-피페라진-1-일)-N-(2-메톡시페닐)-3-니트로벤젠술폰아미드 (반응식 5, 방법 5)4- (trans-2,5-dimethyl-piperazin-1-yl) -N- (2-methoxyphenyl) -3-nitrobenzenesulfonamide (Scheme 5, method 5)

화합물을 중간체 17 및 4-(트란스-2,5-디메틸피페라진으로부터 제조하여, 409 mg 의 황색 고체를 수득했다 (97%): The compound was prepared from intermediates 17 and 4- (trans-2,5-dimethylpiperazine) to give 409 mg of a yellow solid (97%):

Figure 112003042468427-pct00136
Figure 112003042468427-pct00136

아미노기의 환원을 위한 일반적인 과정 (반응식 5, 방법 5) General procedure for the reduction of amino groups (Scheme 5, Method 5)

니트로 화합물 (0.25 mmol) 의 THF (10 mL) 및 메탄올 (2 mL) 중 용액을 라니-Ni (100 mg) 및 히드라진 모노수화물 (120 ㎕, 2.5 mmol) 로 처리했다. 실온에서 7 시간 동안 교반한 후 현탁액을 셀라이트로 여과하고, 에틸 아세테이트 및 에탄올로 세척했다. 에테르 중 HCl 을 사용한 증발로 생성물을 수득했다. 일부 생성물은 불순물이 없었으며, 나머지는 HPLC ((YMC combiprep ODS-AQ, 5O × 2Omm I.D.) 로 정제해야 했다. A solution of nitro compound (0.25 mmol) in THF (10 mL) and methanol (2 mL) was treated with Raney-Ni (100 mg) and hydrazine monohydrate (120 μl, 2.5 mmol). After stirring for 7 hours at room temperature the suspension was filtered through celite and washed with ethyl acetate and ethanol. Evaporation with HCl in ether gave the product. Some products were free of impurities and the rest had to be purified by HPLC ((YMC combiprep ODS-AQ, 50 × 20 mm I.D.).

실시예 101 Example 101                 

3-아미노-N-(2-메톡시페닐)-4-(3-메틸-피페라진-1-일)-벤젠술폰아미드 (반응식 5, 방법 5) 3-Amino-N- (2-methoxyphenyl) -4- (3-methyl-piperazin-1-yl) -benzenesulfonamide (Scheme 5, method 5)

화합물을 N-(2-메톡시페닐)-4-(3-메틸피페라진-1-일)-3-니트로-벤젠술폰아미드로부터 제조해 90 mg 의 표제 화합물을 수득했다 (96%). The compound was prepared from N- (2-methoxyphenyl) -4- (3-methylpiperazin-1-yl) -3-nitro-benzenesulfonamide to give 90 mg of the title compound (96%).

Figure 112003042468427-pct00137
Figure 112003042468427-pct00137

실시예 102 Example 102

3-아미노-4-(헥사히드로-피롤로[1,2-a]피라진-2(1H)-일]-N-(2-메톡시페닐)벤젠술폰아미드 (반응식 5, 방법 5) 3-amino-4- (hexahydro-pyrrolo [1,2-a] pyrazin-2 (1H) -yl] -N- (2-methoxyphenyl) benzenesulfonamide (Scheme 5, method 5)

화합물을 4-(헥사히드로-피롤로[1,2-a]피라진-2-일)-N-(2-메톡시페닐)-3-니트로벤젠술폰아미드로부터 제조해 97 mg 의 표제 화합물을 수득했다 (96%). The compound was prepared from 4- (hexahydro-pyrrolo [1,2-a] pyrazin-2-yl) -N- (2-methoxyphenyl) -3-nitrobenzenesulfonamide to give 97 mg of the title compound. (96%).

Figure 112003042468427-pct00138
Figure 112003042468427-pct00138

술폰아미드 양성자가 발견되지 않았다.No sulfonamide protons were found.

Figure 112003042468427-pct00139
Figure 112003042468427-pct00139

실시예 103 Example 103

3-아미노-N-페닐-4-피페라진-1-일-벤젠술폰아미드 히드로클로라이드 (반응식 5, 방법 5) 3-Amino-N-phenyl-4-piperazin-1-yl-benzenesulfonamide hydrochloride (Scheme 5, method 5)

화합물을 N-페닐-4-피페라진-1-일-3-니트로 벤젠술폰아미드로부터 제조하여, 15 mg 의 황색 고체를 수득했다 (18%):The compound was prepared from N-phenyl-4-piperazin-1-yl-3-nitro benzenesulfonamide to give 15 mg of a yellow solid (18%):

Figure 112003042468427-pct00140
Figure 112003042468427-pct00140

실시예 104 Example 104

3-아미노-4-(3-메틸-피페라진-1-일)-N-페닐-벤젠술폰아미드 히드로클로라이드 (반응식 5, 방법 5) 3-Amino-4- (3-methyl-piperazin-1-yl) -N-phenyl-benzenesulfonamide hydrochloride (Scheme 5, method 5)

화합물을 4-(3-메틸-피페라진-1-일)-N-3-니트로페닐벤젠술폰아미드로부터 제조해 33 mg 의 백색 고체를 수득했다 (35%): The compound was prepared from 4- (3-methyl-piperazin-1-yl) -N-3-nitrophenylbenzenesulfonamide to give 33 mg of white solid (35%):

Figure 112003042468427-pct00141
Figure 112003042468427-pct00141

실시예 105 Example 105

3-아미노-4-(4-에틸-피페라진-1-일)-N-페닐-벤젠술폰아미드 히드로클로라이드 (반응식 5, 방법 5) 3-Amino-4- (4-ethyl-piperazin-1-yl) -N-phenyl-benzenesulfonamide hydrochloride (Scheme 5, method 5)

화합물을 3-아미노-4-(4-에틸-피페라진-1-일)-N-페닐벤젠술폰아미드로부터 제조해 32 mg 의 백색 고체를 수득했다 (33%): The compound was prepared from 3-amino-4- (4-ethyl-piperazin-1-yl) -N-phenylbenzenesulfonamide to give 32 mg of white solid (33%):

Figure 112003042468427-pct00142
Figure 112003042468427-pct00142

실시예 106 Example 106

3-아미노-4-(헥사히드로피롤로[1,2-a]피라진-2(1H)-일)-N-페닐-벤젠술폰아미드 히드로클로라이드 (반응식 5, 방법 5)3-Amino-4- (hexahydropyrrolo [1,2-a] pyrazin-2 (1H) -yl) -N-phenyl-benzenesulfonamide hydrochloride (Scheme 5, method 5)

화합물을 4-(헥사히드로피롤로[1,2-a]피라진-2-일)-N-페닐-3-니트로-벤젠술폰아미드로부터 제조해 50 mg 의 백색 고체를 수득했다 (49%):The compound was prepared from 4- (hexahydropyrrolo [1,2-a] pyrazin-2-yl) -N-phenyl-3-nitro-benzenesulfonamide to give 50 mg of white solid (49%):

Figure 112003042468427-pct00143
Figure 112003042468427-pct00143

실시예 107 Example 107

3-아미노-4-(5-메틸-2,5-디아자-비시클로[2.2.1]헵트-2-일)-N-페닐-벤젠술폰아미드 히드로클로라이드 (반응식 5, 방법 5) 3-Amino-4- (5-methyl-2,5-diaza-bicyclo [2.2.1] hept-2-yl) -N-phenyl-benzenesulfonamide hydrochloride (Scheme 5, method 5)

화합물을 4-(5-메틸-2,5-디아자-비시클로[2.2.1]헵트-2-일)-N-페닐-3-니트로벤젠술폰아미드로부터 제조해 40 mg 의 적색 고체를 수득했다 (40%): The compound was prepared from 4- (5-methyl-2,5-diaza-bicyclo [2.2.1] hept-2-yl) -N-phenyl-3-nitrobenzenesulfonamide to give 40 mg of a red solid. Was (40%):

Figure 112003042468427-pct00144
Figure 112003042468427-pct00144

실시예 108 Example 108

3-아미노-4-(트란스-2,5-디메틸-피페라진-1-일)-N-(2-메톡시-페닐)벤젠술폰아미드 히드로클로라이드 (반응식 5, 방법 5) 3-Amino-4- (trans-2,5-dimethyl-piperazin-1-yl) -N- (2-methoxy-phenyl) benzenesulfonamide hydrochloride (Scheme 5, method 5)

화합물을 4-(트란스-2,5-디메틸-피페라진-1-일)-N-(2-메톡시-페닐)-3-니트로 벤젠술폰아미드로부터 제조해 60 mg 의 백색 고체를 수득했다 (61%): The compound was prepared from 4- (trans-2,5-dimethyl-piperazin-1-yl) -N- (2-methoxy-phenyl) -3-nitro benzenesulfonamide to give 60 mg of white solid ( 61%):

Figure 112003042468427-pct00145
Figure 112003042468427-pct00145

실시예 112 Example 112

4-[4-(3,4-디히드로-2H-퀴놀린-1-술포닐)-2-아미노-페닐]-[1,4]디아제판 디트리플루오로아세트산 (반응식 5, 방법 5) 4- [4- (3,4-dihydro-2H-quinoline-1-sulfonyl) -2-amino-phenyl]-[1,4] diazephan ditrifluoroacetic acid (Scheme 5, method 5)

화합물을 1,2,3,4-테트라히드로-퀴놀린 4-클로로-3-니트로벤젠술포닐 클로라이드 및 [1,4]디아제판-1-카르복실산 tert-부틸 에스테르 (430 ㎕, 2.2 mmol) 로부터 제조해 고체로서 수득했다 (63%). The compound was prepared as 1,2,3,4-tetrahydro-quinoline 4-chloro-3-nitrobenzenesulfonyl chloride and [1,4] diazepane-1-carboxylic acid tert-butyl ester (430 μl, 2.2 mmol) Prepared from and obtained as a solid (63%).

Figure 112003042468427-pct00146
Figure 112003042468427-pct00146

실시예 109 Example 109

2-(3-아미노-4-[1,4]디아제판-1-일-벤젠술포닐)-벤즈아미드 디아세트산 (반응식 5, 방법 5) 2- (3-Amino-4- [1,4] diazepan-1-yl-benzenesulfonyl) -benzamide diacetic acid (Scheme 5, method 5)

화합물을 2-아미노-벤즈아미드, 4-클로로-3-니트로벤젠술포닐 클로라이드 및 [1,4]디아제판-1-카르복실산 tert-부틸로부터 제조해 오일로서 수득했다 (1%). The compound was prepared from 2-amino-benzamide, 4-chloro-3-nitrobenzenesulfonyl chloride and [1,4] diazepane-1-carboxylic acid tert-butyl (1%).

Figure 112003042468427-pct00147
Figure 112003042468427-pct00147

실시예 111 Example 111                 

2-[1,4]디아제판-1-일-5-(3,4-디히드로-1H-이소퀴놀린-2-술포닐)-아닐린 디히드로클로라이드 (반응식 5, 방법 5)2- [1,4] diazepan-1-yl-5- (3,4-dihydro-1H-isoquinoline-2-sulfonyl) -aniline dihydrochloride (Scheme 5, method 5)

화합물을 1,2,3,4-테트라히드로-이소퀴놀린, 4-클로로-3-니트로벤젠술포닐 클로라이드 및 [1,4]디아제판-1-카르복실산 tert-부틸 에스테르로부터 제조해, 백색 고체로서 수득했다 (93 %). The compound was prepared from 1,2,3,4-tetrahydro-isoquinoline, 4-chloro-3-nitrobenzenesulfonyl chloride and [1,4] diazepane-1-carboxylic acid tert-butyl ester, white Obtained as a solid (93%).

Figure 112003042468427-pct00148
Figure 112003042468427-pct00148

실시예 110Example 110

4-[4-(3-플루오로-2-메톡시-페닐술파모일)-2-아미노-페닐]-[1,4]디아제판 디트리플루오로아세트산 (반응식 5, 방법 5) 4- [4- (3-Fluoro-2-methoxy-phenylsulfamoyl) -2-amino-phenyl]-[1,4] diazepane ditrifluoroacetic acid (Scheme 5, method 5)

화합물을 3-플루오로-2-메톡시아닐린, 4-클로로-3-니트로벤젠술포닐 클로라이드 및 [1,4]디아제판-1-카르복실산 tert-부틸 에스테르로부터 제조해 고체로서 수득했다 (43%). The compound was prepared from 3-fluoro-2-methoxyaniline, 4-chloro-3-nitrobenzenesulfonyl chloride and [1,4] diazepane-1-carboxylic acid tert-butyl ester to give as a solid ( 43%).

Figure 112003042468427-pct00149
Figure 112003042468427-pct00149

반응식 6, 방법 6 Scheme 6, method 6

Figure 112003042468427-pct00150
Figure 112003042468427-pct00150

반응식 2 에서의 약호. Abbreviation in Scheme 2.

i: Py, CH2Cl2; ii: K2CO3, CH3CN, 디아민 (예를 들어, 호모피페라진); iii: (BOC)20, THF, NaOH; iv: 라니-Ni, 히드라진 모노히드레이트, THF/EtOH; v: 술포닐클로라이드 (Y-SO2-Cl), Py, Et3N, CH2Cl2; vi: HCl 에테르/MeOH i: Py, CH 2 Cl 2 ; ii: K 2 CO 3 , CH 3 CN, diamines (eg homopiperazine); iii: (BOC) 2 0, THF, NaOH; iv: Raney-Ni, hydrazine monohydrate, THF / EtOH; v: sulfonylchloride (Y-SO 2 -Cl), Py, Et 3 N, CH 2 Cl 2 ; vi: HCl ether / MeOH

중간체 27 Intermediate 27

tert-부틸-4-[4-(아닐리노술포닐)-2-니트로페닐]-1,4-디아제판-1-카르복실레이트 (반응식 6, 방법 6)tert-butyl-4- [4- (anilinosulfonyl) -2-nitrophenyl] -1,4-diazepane-1-carboxylate (Scheme 6, method 6)

THF (20.0 mL) 중 디-tert-부틸 디카르보네이트 (0.921 g, 4.22 mmol) 를, THF:물 (30 mL, 1: 1) 에 용해된 4-(1,4-디아제판-1-일)-3-니트로-N-페닐벤젠술폰아미드 (0.530 mg, 1.40 mmol) 및 NaOH (0.140 g, 3.50 mmol) 의 용액에 첨가했다. 용액을 실온에서 3 시간 동안 교반했다. 혼합물을 5 N HCl 로 중화한 후, THF 를 진공 하에 제거했다. 수성상을 CHCl3 (2 ×50 mL) 로 추출하고 유기상을 배합하여, Na2SO4 상에서 건조시키고, 여과하여 농축했다. 플래쉬 칼럼 크로마토그래피 (SiO2, CHCl3/MeOH 9.75:0.25 를 사용함) 로 정제하여 고체를 수득하여, EtOAc/펜탄으로 연화하여 0.605 g (90%) 의 순수한 생성물을 수득했다. Di-tert-butyl dicarbonate (0.921 g, 4.22 mmol) in THF (20.0 mL) dissolved in THF: water (30 mL, 1: 1) 4- (1,4-diazepane-1-yl ) -3-nitro-N-phenylbenzenesulfonamide (0.530 mg, 1.40 mmol) and NaOH (0.140 g, 3.50 mmol) were added to a solution. The solution was stirred at rt for 3 h. After neutralizing the mixture with 5 N HCl, THF was removed under vacuum. The aqueous phase was extracted with CHCl 3 (2 × 50 mL) and the organic phases combined, dried over Na 2 SO 4 , filtered and concentrated. Purification by flash column chromatography (using SiO 2 , CHCl 3 / MeOH 9.75: 0.25) gave a solid, which was triturated with EtOAc / pentane to give 0.605 g (90%) of the pure product.

Figure 112003042468427-pct00151
Figure 112003042468427-pct00151

tert-부틸-4-[2-니트로-4-(아닐리노술포닐)페닐]-1,4-디아제판-1-카르복실레이트를 라니-Ni 및 히드라진 모노수화물로 처리해 방법 C 로 최종 생성물로 환원하여 유리된 염기 0.477 g 를 수득했다 (91 %); tert-Butyl-4- [2-nitro-4- (anilinosulfonyl) phenyl] -1,4-diazepane-1-carboxylate was treated with Rani-Ni and hydrazine monohydrate to obtain the final product in Method C. Reduction to afford 0.477 g of free base (91%);

Figure 112003042468427-pct00152
Figure 112003042468427-pct00152

실시예 97 Example 97

4-(1,4-디아제판-1-일)-N-페닐-3-[(메틸술포닐)아미노]벤젠술폰아미드 히드로클로라이드 (반응식 6, 방법 6)4- (1,4-diazepane-1-yl) -N-phenyl-3-[(methylsulfonyl) amino] benzenesulfonamide hydrochloride (Scheme 6, method 6)

tert-부틸 4-[2-아미노-4-(아닐리노술포닐)페닐]-1,4-디아제판-1-카르복실레이트 (176 mg, 0.39 mmol), 메틸술파모일 클로라이드 (0.040 mL, 0.47 mmol) 및 피리딘 (0.285 mL, 3.51 mmol) 의 CH2Cl2 (5 mL) 중 혼합물을 실온에서 밤새 교반했다. 반응 혼합물을 NaHCO3 aq (3 x 30 mL) 로 급냉했다. 유기상을 분리하고, 건조 (MgSO4) 시키고, 여과했다. 휘발 물질을 증발시킨 후, 오일 잔사를 크로마토그래피 (SiO2, 헥산/EtOAc 4:1) 로 정제하여 110 mg 의 tert-부틸 4-{4-(아닐리노술포닐)-2-[(메틸술포닐)아미노]페닐}-1,4-디아제판-1-카르복실레이트를 수득했다 (수율 58 %). tert-butyl 4- [2-amino-4- (anilinosulfonyl) phenyl] -1,4-diazepane-1-carboxylate (176 mg, 0.39 mmol), methylsulfamoyl chloride (0.040 mL, 0.47 mmol) and pyridine (0.285 mL, 3.51 mmol) in CH 2 Cl 2 (5 mL) was stirred at rt overnight. The reaction mixture was quenched with NaHCO 3 aq (3 × 30 mL). The organic phase was separated, dried (MgSO 4 ) and filtered. After evaporating the volatiles, the oil residue was purified by chromatography (SiO 2 , hexane / EtOAc 4: 1) to give 110 mg tert-butyl 4- {4- (anilinosulfonyl) -2-[(methylsul Ponyl) amino] phenyl} -1,4-diazepane-1-carboxylate was obtained (yield 58%).

Figure 112003042468427-pct00153
Figure 112003042468427-pct00153

tert-부틸 4-{4-(아닐리노술포닐)-2-[(메틸술포닐)아미노]페닐}-1,4-디아제판-1-카르복실레이트 (0.077 g, 0.147 mmol) 를 MeOH 에 용해한 후, HCl 로 포화된 에테르 기체를 첨가했다. 혼합물을 실온에서 4 시간 동안 교반하고, 농축했다. 미정제 고체를 소량의 MeOH 에 용해하고, 에테르를 첨가했다. 침전을 회수하고, 건조시켜 30 mg 의 순수한 생성물을 HCl 염으로 수득했다 (수율 48%): tert-butyl 4- {4- (anilinosulfonyl) -2-[(methylsulfonyl) amino] phenyl} -1,4-diazepane-1-carboxylate (0.077 g, 0.147 mmol) in MeOH After dissolution, ether gas saturated with HCl was added. The mixture was stirred at rt for 4 h and concentrated. The crude solid was dissolved in a small amount of MeOH and ether was added. The precipitate was recovered and dried to give 30 mg of pure product as HCl salt (yield 48%):

Figure 112003042468427-pct00154
Figure 112003042468427-pct00154

실시예 96 Example 96

4-(1,4-디아제판-1-일)-N-페닐-3-[(페닐술포닐)아미노]벤젠술폰아미드 히드로클로라이드 (반응식 6, 방법 6)4- (1,4-diazepane-1-yl) -N-phenyl-3-[(phenylsulfonyl) amino] benzenesulfonamide hydrochloride (Scheme 6, method 6)

tert-부틸 4-[2-아미노-4-(아닐리노술포닐)페닐]-1,4-디아제판-1-카르복실레이트 (0.268 g, 0.599 mmol), 피리딘 (338 ㎕, 4.19 mmol) 및 Et3N (337 ㎕, 2.40 mmol) 의 CH2Cl2 (8.0 mL) 중 용액에 CH2Cl2 (2 mL) 중 벤젠술포닐 클로라이드 (153 ㎕, 1.20 mmol) 를 첨가했다. 혼합물을 실온에서 16 시간 동안 교반했다. 반응 혼합물을 포화 NaHCO3 수용액으로 세척하고, Na2SO4 으로 건조하고, 여과하여 농축했다. 미정제 물질을 EtOH (5 mL) 에 용해시켜 KOH (0.134 g, 4.0 당량) 를 첨가했다. 반응물을 실온에서 2 일 동안 교반했다. 물 (5 mL) 을 반응 혼합물에 첨가하고, 대부분의 EtOH 를 진공 하에 증발시켰다. 수성상을 CH2Cl2 (3 ×2O mL) 로 추출했다. 조합한 유기상을 Na2SO4 로 건조시키고, 여과시키고 농축했다. 미정제 boc-보호 물질을 MeOH 에 용해하고, HCl 기체로 포화된 에테르를 첨가했다. 혼합물을 16 시간 동안 교반한 후, 농축하여, 0.543 g 의 미정제 생성물을 수득하고, 이를 역상 예비 HPLC 로 정제해 0.153 g 의 순수한 생성물을 아세트산 염으로서 수득해 HCl-염으로 전환시켰다: tert-butyl 4- [2-amino-4- (anilinosulfonyl) phenyl] -1,4-diazepane-1-carboxylate (0.268 g, 0.599 mmol), pyridine (338 μl, 4.19 mmol) and To a solution of Et 3 N (337 μl, 2.40 mmol) in CH 2 Cl 2 (8.0 mL) was added benzenesulfonyl chloride (153 μl, 1.20 mmol) in CH 2 Cl 2 (2 mL). The mixture was stirred at rt for 16 h. The reaction mixture was washed with saturated aqueous NaHCO 3 , dried over Na 2 SO 4 , filtered and concentrated. The crude material was dissolved in EtOH (5 mL) and KOH (0.134 g, 4.0 equiv) was added. The reaction was stirred at rt for 2 days. Water (5 mL) was added to the reaction mixture and most of the EtOH was evaporated in vacuo. The aqueous phase was extracted with CH 2 Cl 2 (3 × 20 mL). The combined organic phases were dried over Na 2 S0 4 , filtered and concentrated. The crude boc-protective material was dissolved in MeOH and ether saturated with HCl gas was added. The mixture was stirred for 16 h and then concentrated to yield 0.543 g of crude product which was purified by reverse phase preparative HPLC to give 0.153 g of pure product as acetic acid salt which was converted to HCl-salts:

Figure 112003042468427-pct00155
Figure 112003042468427-pct00155

중간체 28Intermediate 28

N-나프탈렌-1-일-3-니트로-4-피페라진-1-일-벤젠술폰아미드, 히드로클로라이드 N-naphthalen-1-yl-3-nitro-4-piperazin-1-yl-benzenesulfonamide, hydrochloride

4-클로로-3-니트로벤젠술포닐 클로라이드 (0.992 g, 3.87 mmol) 를, 나프탈렌-1-일아민 (0.665 g, 4.64 mmol) 및 피리딘 (3.1 mL, 38.7 mmol) 의 DCM (5 mL) 중 용액에 첨가했다. 용액을 실온에서 2 일 동안 교반하고, 휘발물질을 증발시켰다. 미정제 혼합물을 EtOAc 에 용해시키고, 유기상을 1 N HCl 로 세척하고, MgSO4 로 건조시키고, 여과시키고 농축하여 1.1 g 의 나프탈렌-1-일-3-니트로-4-클로로-벤젠술폰아미드를 수득했다. 나프탈렌-1-일-3-니트로-4-클로로벤젠술폰아미드를 CH3CN (10 mL) 에 용해시키고, 피페라진 (0.683 g, 7.93 mmol) 을 첨가했다. 혼합물을 65℃ 에서 16 시간 동안 교반했다. 혼합물을 농축하고, 미정제 생성물을, DCM → DCM/MeOH (10%) + 수성 NH3 (0.4%) 을 용출액으로 사용하는 실리카 상의 플래쉬 크로마토그래피로 정제하여 0.531 g 의 유리된 염기를 수득해, 그의 HCl-염으로 전환했다. 4-chloro-3-nitrobenzenesulfonyl chloride (0.992 g, 3.87 mmol) was dissolved in DCM (5 mL) of naphthalen-1-ylamine (0.665 g, 4.64 mmol) and pyridine (3.1 mL, 38.7 mmol). Added to. The solution was stirred for 2 days at room temperature and the volatiles were evaporated. The crude mixture is dissolved in EtOAc, the organic phase is washed with 1N HCl, dried over MgSO 4 , filtered and concentrated to give 1.1 g of naphthalen-1-yl-3-nitro-4-chloro-benzenesulfonamide. did. Naphthalen-1-yl-3-nitro-4-chlorobenzenesulfonamide was dissolved in CH 3 CN (10 mL) and piperazine (0.683 g, 7.93 mmol) was added. The mixture was stirred at 65 ° C. for 16 h. The mixture was concentrated and the crude product was purified by flash chromatography on silica using DCM → DCM / MeOH (10%) + aqueous NH 3 (0.4%) as eluent to afford 0.531 g of free base, Converted to its HCl-salt.

Figure 112003042468427-pct00156
Figure 112003042468427-pct00156

실시예 113 Example 113

3-아미노-2-클로로-N-나프탈렌-1-일-4-피페라진-1-일-벤젠술폰아미드, 히드로클로라이드 3-Amino-2-chloro-N-naphthalen-1-yl-4-piperazin-1-yl-benzenesulfonamide, hydrochloride

N-나프탈렌-1-일-3-니트로-4-피페라진-1-일-벤젠술폰아미드 (0.4602 g, 11.2 mmol) 의 40 mL 4:1 EtOH:THF 용매계 중 용액에 라니-Ni (EtOH 중 ~ 1.0 mL 현탁액) 을 첨가한 후, 히드라진 모노수화물 (2.80 g, 56.0 mmol) 을 첨가했다. 혼합물을 세게 3 시간 동안 교반한 후, 셀라이트로 여과했다. 여과물을 농축하고, 미정제 생성물을 MeOH/에테르로 연화했다. 생성물을 그의 HCl-염으로 전환했다. 유리된 염기로서의 수율 (90%). 한 분취물을 예비 LC/MS 로 정제했다.Rani-Ni (EtOH) in a solution of 40 mL 4: 1 EtOH: THF solvent system of N-naphthalen-1-yl-3-nitro-4-piperazin-1-yl-benzenesulfonamide (0.4602 g, 11.2 mmol) Medium to 1.0 mL suspension), followed by hydrazine monohydrate (2.80 g, 56.0 mmol). The mixture was stirred vigorously for 3 hours and then filtered through celite. The filtrate was concentrated and the crude product was triturated with MeOH / ether. The product was converted to its HCl-salt. Yield as free base (90%). One aliquot was purified by preparative LC / MS.

Figure 112003042468427-pct00157
Figure 112003042468427-pct00157

생물학적 시험 Biological test

5-HT6 수용체에 결합하는 본 발명의 화합물의 성능, 및 약제학적으로서의 유 용성을 당 분야에 공지된 생체내 및 시험관내 검정으로 결정할 수 있다. The ability of the compounds of the invention to bind 5-HT 6 receptors, and their usefulness as pharmaceuticals, can be determined by in vivo and in vitro assays known in the art.

(a) 5-HT(a) 5-HT 66 내재 활성 검정 Intrinsic Activity Test

5-HT6 수용체에 대한 길항제는, 인간 5-HT6 수용체를 발현하는 HEK 293 세포에서 5-HT 저해로 유도되는 cAMP 증가를 측정함으로써 특징화된다 (참고, Boess 등. (1997) Neuropharmacology 36: 713-720). 간략하게, HEK 293/5-HT6 세포를 25,000 /웰의 밀도로 폴리라이신이 코팅된 96-웰 플레이트에 시딩 (seeding) 하고, 5% 로 투석된 소태아 혈청을 함유하는 DMEM (Dulbecco's Modified Eagle Medium) (페놀레드가 없음) 중에 48 시간 동안 37℃ 에서 5% CO2 인큐베이터 내에서 배양했다. 이어서, 배지를 흡출해내고, 0.1 ml 의 검정 배지로 바꿨다 (20 mM HEPES, 1.5 mM 이소부틸메틸잰틴 및 1 mg/ml 소 혈청 알부민을 함유하는 Hanks Balance Salt Solution). 시험 물질 50 ㎕를 검정 배지에 용해하여 첨가한 후, 세포를 10 분 동안 37℃ 에서 5% C02 인큐베이터 내에서 배양했다. 배지를 다시 흡출해내고, cAMP 함량을 방사성 cAMP 키트 (Amersharn Pharmacia Biotech, BIOTRAK RPA559) 로 측정했다. 길항제의 효능을 계산식 Ki,eff=IC50/(1+[5HT]/EC50) 를 이용하여, cAMP 의 증가를 유도하는 5-HT 를 50% 저해하는 농도 ([5-HT]= 8 배의 EC50) 를 측정함으로써 정량했다. 5-HT antagonist for the 6 receptor is a human 5-HT 6 is characterized by measuring the cAMP increase induced in HEK 293 cells with 5-HT inhibitory expressing the receptor (see, Boess, etc. (1997) Neuropharmacology 36.: 713-720). Briefly, HEK 293 / 5-HT 6 cells were seeded in polylysine-coated 96-well plates at a density of 25,000 / well and DMEM (Dulbecco's Modified Eagle) containing fetal bovine serum dialyzed at 5% Medium (no phenol red) was incubated in a 5% CO 2 incubator at 37 ° C. for 48 hours. The medium was then aspirated off and replaced with 0.1 ml of assay medium (Hanks Balance Salt Solution containing 20 mM HEPES, 1.5 mM isobutylmethylxanthine and 1 mg / ml bovine serum albumin). After 50 μl of test substance was dissolved and added to the assay medium, the cells were incubated in a 5% CO 2 incubator at 37 ° C. for 10 minutes. The medium was aspirated off again and the cAMP content was measured with a radioactive cAMP kit (Amersharn Pharmacia Biotech, BIOTRAK RPA559). The efficacy of the antagonist was calculated using the formula K i, eff = IC 50 / (1+ [5HT] / EC 50 ) to inhibit 50% of 5-HT inducing an increase in cAMP ([5-HT] = 8). Quantification was performed by measuring EC 50 ) of the embryo.

본 발명에 따른 화합물은 1 nM 내지 5 μM 의 Ki 값으로 5-HT6 수용체에 대한 선택적인 친화성을 가지며, 이들은 cAMP 의 5-HT 지수 증가를 길항한다. Ki 결합지수와 Ki,약효 사이에는 상관성이 있다. 더욱이, 화합물들은 5-HT2a,, 5-HT 2b, 5-HT2c, 5-HT1a, 5HT1b 에 대한 우수한 선택성 ( >100 배) 을 나타낸다. The compounds according to the invention have a selective affinity for the 5-HT 6 receptor with Ki values between 1 nM and 5 μM, which antagonize the 5-HT index increase of cAMP. There is a correlation between Ki binding index and K i, efficacy . Moreover, the compounds show good selectivity (> 100 fold) for 5-HT 2a , 5-HT 2b , 5-HT 2c , 5-HT 1a , 5HT 1b .

(b) 식량 섭취 감소의 생체내 시험 (b) In vivo testing of reduced food intake

세로토닌 및 식량 섭취에 대한 리뷰로서, 문헌 [Blundell, J.E. 및 Halford, J.C.G. (1998) Serotonin and Appetite Regulation. Implications for the Pharmacological Treatment of Obesity. CNS Drugs 9:473-495] 를 참조한다. As a review of serotonin and food intake, see Blundell, J.E. And Halford, J.C.G. (1998) Serotonin and Appetite Regulation. Implications for the Pharmacological Treatment of Obesity. CNS Drugs 9: 473-495.

비만 (ob/ob) 마우스는, 노이즈 비율에 대한 높은 시그날을 초래하는 다량의 식량을 소비하는 돌연변이 마우스이기 때문에, 우선적인 동물 모델로서 선택된다. 약효 데이타를 더 입증하고 비교하기 위해, 식량 소비에 대한 화합물의 영향을 또한 야생형 (C57BL/6J) 마우스에서도 연구했다. 화합물 주입 15 시간 동안 소비되는 식품의 양을 기록했다.Obese (ob / ob) mice are selected as preferential animal models because they are mutant mice that consume large amounts of food resulting in a high signal for noise ratio. To further validate and compare drug efficacy data, the effect of the compound on food consumption was also studied in wild-type (C57BL / 6J) mice. The amount of food consumed for 15 hours of compound injection was recorded.

평균 체중이 50 g (비만) 및 25 g (마름) 인 수컷 마우스 (비만 C57BL/6JBom-Lepob 및 마른 야생형 C57Bl/6JBom; Bomholtsgaard, 덴마크) 8-9 주령을 모든 연구에서 사용했다. 동물들을 23 ±1℃, 습도 40-60 % 에서 우리 안에 1 마리씩 사육하고, 물에 대한 자유 접근을 허용하고 표준 실험실 사료를 먹게 했다. 12/12 시간 밝음/어두움 주기를 정해 오후 5 시에 소등했다. 동물들을 연구 시작 적어도 1 주 전에 조건화했다.Male mice with an average body weight of 50 g (obesity) and 25 g (dry) (obesity C57BL / 6JBom-Lep ob and lean wild-type C57Bl / 6JBom; Bomholtsgaard, Denmark) 8-9 weeks old were used in all studies. Animals were housed in cages at 23 ± 1 ° C and 40-60% humidity, allowing free access to water and eating standard laboratory feed. The 12/12 hour light / dark cycle was turned off at 5 pm. The animals were conditioned at least 1 week before the start of the study.

시험 화합물을, 각각의 구체적인 화합물에 적합한 용매, 예컨대 시클로덱스트린, 시클로덱스트린/메탄 황산, 폴리에틸렌 글리콜/메탄 술폰산, 식염수에 용해 시켰다. 각각의 연구에서 용액을 새로 만든다. 투여량 30, 50 및 100 mg/kg/1 일을 사용했다. 시험 화합물을 순도는 분석 등급이었다. Test compounds were dissolved in a solvent suitable for each specific compound, such as cyclodextrin, cyclodextrin / methane sulfuric acid, polyethylene glycol / methane sulfonic acid, saline. In each study, a new solution is made. Doses 30, 50 and 100 mg / kg / 1 day were used. The purity of the test compound was analytical grade.

동물들은 연구 시작시 체중 칭량을 하고, 체중을 기준으로 랜덤화했다. Alzet osmotic minipumps (Model 2001D; 주입 속도 8 ㎕/시간) 을 사용하여, 본질적으로 Alzet technical information manual (Alza Scientific Products, 1997; Teeuwes and Yam, 1976) 에서 권장된 바와 같이 주입했다. 24 시간 연속 피하 주입을 사용했다. 미니펌프는 비히클에 용해된 상이한 농도의 시험 화합물 또는 비히클 용액으로만 채웠으며, 비히클을 37℃ 로 예열해 유지했다 (약 1 시간). 미니펌프를 단기 작용 마취 (메토판/엔플루란) 하에 목/등 부분에 피하 이식했다. 상기 외과적 과정은 약 5 분 지속했다. 화합물의 정적 상태 전달에는 약 3 시간이 걸렸다. Animals were weighed at the beginning of the study and randomized based on body weight. Alzet osmotic minipumps (Model 2001D; infusion rate 8 μl / hour) were used to inject essentially as recommended in the Alzet technical information manual (Alza Scientific Products, 1997; Teeuwes and Yam, 1976). 24 hours continuous subcutaneous infusion was used. The minipump was only filled with different concentrations of test compound or vehicle solution dissolved in the vehicle and the vehicle was preheated and maintained at 37 ° C. (about 1 hour). Minipumps were implanted subcutaneously in the neck / dorm under short acting anesthesia (Metophan / Enflurane). The surgical procedure lasted about 5 minutes. The static state delivery of the compound took about 3 hours.

식품 펠렛의 중량을, 삼투압 미니펌프 (osmotic minipump) 이식 전 (기준선) 2 일간 및 이식 후 1 일간 오후 5 시 및 오후 8 시에 측정했다. 중량 검사는 컴퓨터 보조 Mettler Toledo PR 5002 balance 를 이용해 수행했다. 우발적인 유출은 정정되었다. 연구 말기에, 동물들은 경추 이탈로 희생시켰으며, 동맥간혈을 이후의 혈청 약물 농도 분석을 위해 채취했다. The weight of the food pellets was measured at 5 pm and 8 pm 2 days prior to osmotic minipump implantation (baseline) and 1 day after transplantation. The weight test was performed using a computer assisted Mettler Toledo PR 5002 balance. Accidental spills were corrected. At the end of the study, animals were sacrificed for cervical dislocation and arterial hepatic blood was collected for subsequent serum drug concentration analysis.

혈청 샘플 단백질을 메탄올로 침전시키고, 원심분리하고 상층액을 HPLC 바이알에 옮겨, 액체 크로마토그래피/질량 분광계에 넣었다. 질량 분광계는 전자분사 양이온 모드 (electrospray positive ion mode) 및 Multiple Reaction Monitoring (전이가 m/z 316 => 221 인 MRM) 으로 고정했다. Serum sample proteins were precipitated with methanol, centrifuged and the supernatants transferred to HPLC vials and placed in a liquid chromatography / mass spectrometer. The mass spectrometer was fixed in electrospray positive ion mode and Multiple Reaction Monitoring (MRM with transition m / z 316 => 221).                 

원점을 지나는 표준값의 선형 회귀 분석이 미지 샘플의 농도 계산에 사용되었다. Linear regression analysis of the standard values past the origin was used to calculate the concentration of the unknown samples.

15 시간 동안의 식량 소비를 연속하는 3 일 동안 측정하고, 기본값의 백분율을, 처리 전후부터 각각의 동물에 대해 산출했다. 투여군 당 8 마리의 동물로부터 값들을 평균 ± SD 및 ± SEM 로 나타냈다. 통계적 평가는 백분율 기준 값을 사용하여 Kruskal-Wallis one-way ANOVA 로 수행했다. 통계적 유의성이 p<0.05 의 수준에 이르면, 대조군과 처리군 사이의 통계적 비교를 위한 Mann-Whitney U-시험을 수행했다.Food consumption for 15 hours was measured over three consecutive days, and a percentage of the default value was calculated for each animal from before and after treatment. Values from 8 animals per dose group are expressed as mean ± SD and ± SEM. Statistical evaluation was performed with Kruskal-Wallis one-way ANOVA using percentage reference values. When the statistical significance reached a level of p <0.05, the Mann-Whitney U-test was performed for statistical comparison between the control and treatment groups.

본 발명에 따른 화합물은 50-150 mg/kg 범위에서 약효를 나타낸다. The compounds according to the invention show efficacy in the range of 50-150 mg / kg.

실시예Example 투여량 (mg/Kg)Dose (mg / Kg) 경구 투여 식량 섭취 감소율(%)Oral administration of food intake reduction (%) 2727 5050 2828 2828 100100 6060







Claims (27)

화학식 I 의 화합물 또는 그의 약제학적으로 허용되는 염:Compound of Formula (I) or a pharmaceutically acceptable salt thereof: [화학식 I][Formula I]
Figure 112008080077431-pct00166
Figure 112008080077431-pct00166
 [식 중, X 는 하기이며: [Wherein X is: [화학식 Ia]Formula Ia
Figure 112008080077431-pct00167
Figure 112008080077431-pct00167
 [화학식 Ib]Formula Ib
Figure 112008080077431-pct00168
Figure 112008080077431-pct00168
 R1 및 R3 는 독립적으로 R 1 and R 3 are independently (a) H (a) H (b) C1-6 알킬, (b) C 1-6 alkyl, (C) C1-6 알콕시, (C) C 1-6 alkoxy, (d) 직쇄형 또는 분지형 C1-6 히드록시알킬, (d) straight or branched C 1-6 hydroxyalkyl, (e) 직쇄형 또는 분지형 C1-6 알킬할라이드; 또는 (e) straight or branched C 1-6 alkyl halides; or (f) 기 Ar 이며; (f) the group Ar; Ar 은 Ar is (a) 페닐, (a) phenyl, (b) 1-나프틸, (b) 1-naphthyl, (c) 2-나프틸, (c) 2-naphthyl, (d) 벤질, (d) benzyl, (e) 시나밀 (cinnamyl), (e) cinnamil, (f) 5 내지 7 원의, 부분적으로 또는 완전히 포화된, 산소, 질소 및 황으로부터 선택되는 1 내지 4 개의 헤테로원자를 포함하는 복소환이거나, 또는 (f) a 5 to 7 membered, partially or fully saturated heterocycle containing 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur, or (g) (f) 에서 정의된 바와 같은 복소환 2 개로 이루어진 이환 고리계이거나, 또는 하나의 벤젠 고리 및 (f) 에서 정의된 바와 같은 하나의 복소환으로 이루어진 이환 고리계이며; (g) a bicyclic ring system consisting of two heterocycles as defined in (f) or a bicyclic ring system consisting of one benzene ring and one heterocycle as defined in (f); 대안적으로는, R1 및 R3 은 연결되어 화학식 Ib 에서 기 (CH2)20, (CH2)40, 또는 (CH2)3-5 를 형성하며; Alternatively, R 1 and R 3 are joined to form a group (CH 2 ) 2 0, (CH 2 ) 4 0, or (CH 2 ) 3-5 in formula Ib; 임의로는, 기 Ar 가 하기로 치환되며: Optionally, the group Ar is substituted with: (a) Y, 또는(a) Y, or (b) 5 내지 7 원의, 부분적으로 또는 완전히 포화된, 각각 산소, 질소 또는 황으로부터 선택되는 1 내지 4 개의 헤테로원자를 포함하는 복소환이며;(b) a 5 to 7 membered, partially or fully saturated heterocycle containing 1 to 4 heteroatoms each selected from oxygen, nitrogen or sulfur; Y 는 Y is (a) H, (a) H, (b) 할로겐, (b) halogen, (c) C1-6 알킬, (c) C 1-6 alkyl, (d) CF3, (d) CF 3 , (e) 히드록시, (e) hydroxy, (f) C1-6 알콕시, (f) C 1-6 alkoxy, (g) C1-4 알케닐; (g) C 1-4 alkenyl; (h) 페닐; (h) phenyl; (i) 페녹시, (i) phenoxy, (j) 벤질옥시, (j) benzyloxy, (l) OCF3, (l) OCF 3 , (m) CN, (m) CN, (n) 직쇄형 또는 분지형 C1-6 히드록시알킬, (n) straight or branched C 1-6 hydroxyalkyl, (o) 직쇄형 또는 분지형 C1-6 알킬할라이드, (o) straight or branched C 1-6 alkyl halides, (p) NH2, (p) NH 2 , (q) NHR6,(q) NHR 6 , (r) NR6R7, (r) NR 6 R 7 , (s) N02, (s) N0 2 , (u) NHS02R6,(u) NHS0 2 R 6 , (v) NR6COR7 이며; (v) NR 6 COR 7 ; R2 및 R4 는 독립적으로: R 2 and R 4 are independently: (a) -SO2R1, (a) -SO 2 R 1 , (b) H, (b) H, (C) C1-6 알킬, (C) C 1-6 alkyl, (d) C1-C3 알케닐, (d) C 1 -C 3 alkenyl, (e) C1-C3 알킬아릴, (e) C 1 -C 3 alkylaryl, (f) Ar 로서, R1 에 대해 상기 정의된 것, (f) Ar, as defined above for R 1 , (g) -C(=O)R6, (g) -C (= 0) R 6 , (h) -C(O)NR6R7, (h) -C (O) NR 6 R 7 , (i) -C(S)NR6R7, (i) -C (S) NR 6 R 7 , (j) -CO2R6; (j) -CO 2 R 6 ; (k) -C(S)R6; (k) -C (S) R 6 ; (l) 직쇄형 또는 분지형 C1-6 히드록시알킬이거나, 또는 (l) straight or branched C 1-6 hydroxyalkyl, or (m) 직쇄형 또는 분지형 C1-6 알킬할라이드이며; (m) straight or branched C 1-6 alkyl halides; 대안적으로는, R2 및 R4 는 연결되어 화학식 Ia 에서 기 (CH2)20, (CH2)40 또는 (CH2)3-5 를 형성하며;Alternatively, R 2 and R 4 are joined to form a group (CH 2 ) 2 0, (CH 2 ) 4 0 or (CH 2 ) 3-5 in formula (Ia); R5 는 하기 화학기로 이루어지는 군으로부터 선택되며:R 5 is selected from the group consisting of:
Figure 112008080077431-pct00184
R6 및 R7 는 독립적으로 하기이며:
Figure 112008080077431-pct00184
R 6 and R 7 are independently (a) H, (a) H, (b) C1-6 알킬, (b) C 1-6 alkyl, (C) C3-7 시클로알킬, 또는 (C) C 3-7 cycloalkyl, or (d) Ar 로서, R1 에 대해 상기 정의된 것; (d) Ar, as defined above for R 1 ; 대안적으로는, R6 및 R7 는 연결되어 기 (CH2)20, (CH2)40 또는 (CH2)3-5 를 형성하며; Alternatively, R 6 and R 7 are joined to form a group (CH 2 ) 2 0, (CH 2 ) 4 0 or (CH 2 ) 3-5 ; R8 은 R 8 is (a) H, 또는 (a) H, or (b) C1-6 알킬이다]. (b) C 1-6 alkyl]. 제 1 항에 있어서, 하기를 만족하는 화합물:A compound according to claim 1 which satisfies: R1 은 기 Ar 이며; R 1 is a group Ar; Ar 은 Ar is (a) 페닐, (a) phenyl, (b) 1 -나프틸, (b) 1 -naphthyl, (c) 2-나프틸, 또는 (c) 2-naphthyl, or (f) 5 내지 7 원의, 부분적으로 또는 완전히 포화된, 산소, 질소 및 황으로부터 선택되는 1 내지 4 개의 헤테로원자를 포함하는 복소환이며; (f) a 5 to 7 membered, heterocyclic ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur, partially or fully saturated; 기 Ar 은 Y 로 치환되며, The group Ar is substituted with Y, Y 는 Y is (a) H, (a) H, (b) 할로겐, (b) halogen, (C) C1-6 알킬, (C) C 1-6 alkyl, (d) CF3, (d) CF 3 , (f) C1-6 알콕시, (f) C 1-6 alkoxy, (g) C1-4 알케닐; (g) C 1-4 alkenyl; (h) 페닐; (h) phenyl; (1) OCF3, 또는 (1) OCF 3 , or (n) 직쇄형 또는 분지형 C1-6 히드록시알킬이다. (n) straight or branched C 1-6 hydroxyalkyl. 제 1 항 또는 제 2 항에 있어서, 기
Figure 112003042530326-pct00170
가 페닐 고리의 2-위치 및 3-위치에 결합하는 화합물.The process according to claim 1 or 2, wherein
Figure 112003042530326-pct00170
To bond to the 2- and 3-positions of the phenyl ring. 제 1 항 또는 제 2 항에 있어서, R2 가 -SO2R1 인 화합물. The compound of claim 1 or 2, wherein R 2 is —SO 2 R 1 . 제 1 항 또는 제 2 항에 있어서, R2 및 R4 가 독립적으로 H, 메틸 또는 에틸인 화합물. The compound of claim 1 or 2, wherein R 2 and R 4 are independently H, methyl or ethyl. 제 1 항 또는 제 2 항에 있어서, R5 가 하기의 화학기로 이루어진 군으로부터 선택되는 화합물:The compound according to claim 1 or 2, wherein R 5 is selected from the group consisting of the following chemical groups:
Figure 112007033836576-pct00171
Figure 112007033836576-pct00171
 [식 중, R8 은 H 또는 메틸이다]. [Wherein R 8 is H or methyl]. 제 1 항 또는 제 2 항에 있어서, R6 및 R7 가 독립적으로 하기인 화합물:The compound of claim 1 or 2, wherein R 6 and R 7 are independently (a) H, (a) H, (b) C1-6 알킬, (b) C 1-6 alkyl, (c) C3-7 시클로알킬, 또는(c) C 3-7 cycloalkyl, or (d) Ar. (d) Ar. 하기의 화합물 또는 그의 약제학적으로 허용되는 염:      The following compounds or pharmaceutically acceptable salts thereof: N-[2-{에틸[(3-플루오로페닐)술포닐]아미노}-4-(4-메틸-1-피페라지닐)페닐] -3-플루오로벤젠술폰아미드, N- [2- {ethyl [(3-fluorophenyl) sulfonyl] amino} -4- (4-methyl-1-piperazinyl) phenyl] -3-fluorobenzenesulfonamide, N-[2-[에틸(페닐술포닐)아미노]-4-(4-메틸-1-피페라지닐)페닐] 벤젠술폰아미드, N- [2- [ethyl (phenylsulfonyl) amino] -4- (4-methyl-1-piperazinyl) phenyl] benzenesulfonamide, 3-플루오로-N-[2-{[(3-플루오로페닐)술포닐]아미노}-4-(4-메틸-1-피페라지닐)페닐]벤젠술폰아미드, 3-fluoro-N- [2-{[(3-fluorophenyl) sulfonyl] amino} -4- (4-methyl-1-piperazinyl) phenyl] benzenesulfonamide, N-{5-(4-메틸-1-피페라지닐)-2-[(8-퀴놀리닐술포닐)아미노]페닐}-7-퀴놀린술폰아미드, N- {5- (4-methyl-1-piperazinyl) -2-[(8-quinolinylsulfonyl) amino] phenyl} -7-quinolinesulfonamide, N-[2-클로로-4-({4-(4-메틸-1-피페라지닐)-2-[(페닐술포닐)아미노]아닐리노}술포닐)페닐]아세트아미드, N- [2-chloro-4-({4- (4-methyl-1-piperazinyl) -2-[(phenylsulfonyl) amino] anilino} sulfonyl) phenyl] acetamide, 3,4-디메톡시-N-{4-(4-메틸-1-피페라지닐)-2-[(페닐술포닐)아미노]페닐}벤젠술폰아미드, 3,4-dimethoxy-N- {4- (4-methyl-1-piperazinyl) -2-[(phenylsulfonyl) amino] phenyl} benzenesulfonamide, 3-메톡시-4-메틸-N-{4-(4-메틸-1-피페라지닐)-2-[(페닐술포닐)아미노]페닐} 벤젠술폰아미드, 3-methoxy-4-methyl-N- {4- (4-methyl-1-piperazinyl) -2-[(phenylsulfonyl) amino] phenyl} benzenesulfonamide, 4-메틸-N-{4-(4-메틸-1-피페라지닐)-2-[(메틸술포닐)아미노]페닐}벤젠술폰아미드, 4-methyl-N- {4- (4-methyl-1-piperazinyl) -2-[(methylsulfonyl) amino] phenyl} benzenesulfonamide, 3,4-디메톡시-N-{4-(4-메틸-1-피페라지닐)-2-[(메틸술포닐)아미노]페닐}벤젠술폰아미드, 3,4-dimethoxy-N- {4- (4-methyl-1-piperazinyl) -2-[(methylsulfonyl) amino] phenyl} benzenesulfonamide, 3-시아노-N-{4-(4-메틸-1-피페라지닐)-2-[(메틸술포닐)아미노]페닐}벤젠술폰아미드, 3-cyano-N- {4- (4-methyl-1-piperazinyl) -2-[(methylsulfonyl) amino] phenyl} benzenesulfonamide, N-{4-(1-피페라지닐)-2-[(페닐술포닐)아미노]페닐}-1-나프탈렌술폰아미드, N- {4- (1-piperazinyl) -2-[(phenylsulfonyl) amino] phenyl} -1-naphthalenesulfonamide, 5-(디메틸아미노)-N-{4-(1-피페라지닐)-2-[(페닐술포닐)아미노]페닐}-1-나프탈렌술폰아미드, 5- (dimethylamino) -N- {4- (1-piperazinyl) -2-[(phenylsulfonyl) amino] phenyl} -1-naphthalenesulfonamide, N-[2-[(페닐술포닐)아미노]-4-(1-피페라지닐)페닐]-8-퀴놀린술폰아미드,N- [2-[(phenylsulfonyl) amino] -4- (1-piperazinyl) phenyl] -8-quinolinesulfonamide, 2,4,6-트리메틸-N-[2-[(페닐술포닐)아미노]-4-(1-피페라지닐)페닐]벤젠술폰아미드, 2,4,6-trimethyl-N- [2-[(phenylsulfonyl) amino] -4- (1-piperazinyl) phenyl] benzenesulfonamide, 4-메틸-N-[2-[(페닐술포닐)아미노]-4-(1-피페라지닐)페닐]벤젠술폰아미드,4-methyl-N- [2-[(phenylsulfonyl) amino] -4- (1-piperazinyl) phenyl] benzenesulfonamide, N-[2-({[(E)-2-페닐에테닐]술포닐}아미노)-5-(1-피페라지닐)페닐]벤젠술폰아미드, N- [2-({[(E) -2-phenylethenyl] sulfonyl} amino) -5- (1-piperazinyl) phenyl] benzenesulfonamide, 2,5-디메톡시-N-[2-[(페닐술포닐)아미노]-4-(1-피페라지닐)페닐]벤젠술폰아미드, 2,5-dimethoxy-N- [2-[(phenylsulfonyl) amino] -4- (1-piperazinyl) phenyl] benzenesulfonamide, 2-메틸-N-[2-[(페닐술포닐)아미노]-4-(1-피페라지닐)페닐]벤젠술폰아미드,2-methyl-N- [2-[(phenylsulfonyl) amino] -4- (1-piperazinyl) phenyl] benzenesulfonamide, 2,4-디플루오로-N-[2-[(페닐술포닐)아미노]-4-(1-피페라지닐)페닐]벤젠술폰아미드, 2,4-difluoro-N- [2-[(phenylsulfonyl) amino] -4- (1-piperazinyl) phenyl] benzenesulfonamide, 4-부톡시-N-[2-[(페닐술포닐)아미노]-4-(1-피페라지닐)페닐]벤젠술폰아미드,4-butoxy-N- [2-[(phenylsulfonyl) amino] -4- (1-piperazinyl) phenyl] benzenesulfonamide, 3,5-디메틸-N-[2-[(페닐술포닐)아미노]-4-(1-피페라지닐)페닐]-4-이속사졸술폰아미드, 3,5-dimethyl-N- [2-[(phenylsulfonyl) amino] -4- (1-piperazinyl) phenyl] -4-isoxazolesulfonamide, 5-플루오로-2-메틸-N-[2-[(페닐술포닐)아미노]-4-(1-피페라지닐)페닐]벤젠술폰아미드, 5-fluoro-2-methyl-N- [2-[(phenylsulfonyl) amino] -4- (1-piperazinyl) phenyl] benzenesulfonamide, 4-(메틸술포닐)-N-[2-[(페닐술포닐)아미노]-4-(1-피페라지닐)페닐]벤젠술폰아미드, 4- (methylsulfonyl) -N- [2-[(phenylsulfonyl) amino] -4- (1-piperazinyl) phenyl] benzenesulfonamide, 2-(메틸술포닐)-N-[2-[(페닐술포닐)아미노]-4-(1-피페라지닐)페닐]벤젠술폰아미드, 2- (methylsulfonyl) -N- [2-[(phenylsulfonyl) amino] -4- (1-piperazinyl) phenyl] benzenesulfonamide, 2-메톡시-4-메틸-N-[2-[(페닐술포닐)아미노]-4-(1-피페라지닐)페닐]벤젠술폰아미드, 2-methoxy-4-methyl-N- [2-[(phenylsulfonyl) amino] -4- (1-piperazinyl) phenyl] benzenesulfonamide, 4-메톡시-2-메틸-N-[2-[(페닐술포닐)아미노]-4-(1-피페라지닐)페닐]벤젠술폰아미드, 4-methoxy-2-methyl-N- [2-[(phenylsulfonyl) amino] -4- (1-piperazinyl) phenyl] benzenesulfonamide, N-[2-아미노-4-(1-피페라지닐)페닐]-3-플루오로벤젠술폰아미드, N- [2-amino-4- (1-piperazinyl) phenyl] -3-fluorobenzenesulfonamide, N-[2-(에틸아미노)-4-(1-피페라지닐)페닐]-3-플루오로벤젠술폰아미드, N- [2- (ethylamino) -4- (1-piperazinyl) phenyl] -3-fluorobenzenesulfonamide, N-{4-(1,4-디아제판-1-일)-2-[(페닐술포닐)아미노]페닐}벤젠술폰아미드 히드로클로라이드, N- {4- (1,4-diazepane-1-yl) -2-[(phenylsulfonyl) amino] phenyl} benzenesulfonamide hydrochloride, N-(4-(1,4-디아제판-1-일)-2-{[(3-플루오로페닐)술포닐]-아미노}페닐)-3-플루오로벤젠술폰아미드 히드로클로라이드, N- (4- (1,4-diazepane-1-yl) -2-{[(3-fluorophenyl) sulfonyl] -amino} phenyl) -3-fluorobenzenesulfonamide hydrochloride, N-{5-(1,4-디아제판-1-일)-2-[(페닐술포닐)아미노]페닐}-N-에틸벤젠술폰아미드 히드로클로라이드, N- {5- (1,4-diazepane-1-yl) -2-[(phenylsulfonyl) amino] phenyl} -N-ethylbenzenesulfonamide hydrochloride, N-{5-(1,4-디아제판-1-일)-2-[(메틸술포닐)아미노]페닐}벤젠술폰아미드 히드로클로라이드, N- {5- (1,4-diazepane-1-yl) -2-[(methylsulfonyl) amino] phenyl} benzenesulfonamide hydrochloride, N-{5-(1,4-디아제판-1-일)-2-[(에틸술포닐)아미노]페닐}벤젠술폰아미드 히드로클로라이드, N- {5- (1,4-diazepane-1-yl) -2-[(ethylsulfonyl) amino] phenyl} benzenesulfonamide hydrochloride, N-{4-(1,4-디아제판-1-일)-2-[(페닐술포닐)아미노]페닐}[1,1'-비페닐]-4-술폰아미드 히드로클로라이드, N- {4- (1,4-diazepane-1-yl) -2-[(phenylsulfonyl) amino] phenyl} [1,1'-biphenyl] -4-sulfonamide hydrochloride, N-{4-(1,4-디아제판-1-일)-2-[(페닐술포닐)아미노]페닐}-2,1,3-벤족사디아졸 -4-술폰아미드 히드로클로라이드, N- {4- (1,4-diazepane-1-yl) -2-[(phenylsulfonyl) amino] phenyl} -2,1,3-benzoxadiazole-4-sulfonamide hydrochloride, N-{4-(1,4-디아제판-1-일)-2-[(페닐술포닐)아미노]페닐}-2-나프탈렌술폰아미드 히드로클로라이드, N- {4- (1,4-diazepane-1-yl) -2-[(phenylsulfonyl) amino] phenyl} -2-naphthalenesulfonamide hydrochloride, N-{4-(1,4-디아제판-1-일)-2-[(메틸술포닐)아미노]페닐}벤젠술폰아미드 히드로클로라이드, N- {4- (1,4-diazepane-1-yl) -2-[(methylsulfonyl) amino] phenyl} benzenesulfonamide hydrochloride, N-{4-(1,4-디아제판-1-일)-2-[메틸(메틸술포닐)아미노]페닐}벤젠술폰아미드 히드로클로라이드, N- {4- (1,4-diazepane-1-yl) -2- [methyl (methylsulfonyl) amino] phenyl} benzenesulfonamide hydrochloride, N-{4-(1,4-디아제판-1-일)-2-[(메틸술포닐)아미노]페닐}-N-메틸벤젠술폰아미드 히드로클로라이드, N- {4- (1,4-diazepane-1-yl) -2-[(methylsulfonyl) amino] phenyl} -N-methylbenzenesulfonamide hydrochloride, N-{4-(1,4-디아제판-1-일)-2-[메틸(페닐술포닐)아미노]페닐}벤젠술폰아미드 히드로클로라이드, N- {4- (1,4-diazepane-1-yl) -2- [methyl (phenylsulfonyl) amino] phenyl} benzenesulfonamide hydrochloride, N-{4-(1,4-디아제판-1-일)-2-[(메틸술포닐)아미노]페닐}-1-나프탈렌술폰아미드 히드로클로라이드, N- {4- (1,4-diazepane-1-yl) -2-[(methylsulfonyl) amino] phenyl} -1-naphthalenesulfonamide hydrochloride, N-{4-(1,4-디아제판-1-일)-2-[(메틸술포닐)아미노]페닐}-2-나프탈렌술폰아미드 히드로클로라이드, N- {4- (1,4-diazepane-1-yl) -2-[(methylsulfonyl) amino] phenyl} -2-naphthalenesulfonamide hydrochloride, N-{4-(1,4-디아제판-1-일)-2-[(메틸술포닐)아미노]페닐}-4-플루오로벤젠술폰아미드 히드로클로라이드, N- {4- (1,4-diazepane-1-yl) -2-[(methylsulfonyl) amino] phenyl} -4-fluorobenzenesulfonamide hydrochloride, N-{4-(1,4-디아제판-1-일)-2-[(메틸술포닐)아미노]페닐}-4-니트로벤젠술폰아미드 히드로클로라이드, N- {4- (1,4-diazepane-1-yl) -2-[(methylsulfonyl) amino] phenyl} -4-nitrobenzenesulfonamide hydrochloride, N-{4-(1,4-디아제판-1-일)-2-[(메틸술포닐)아미노]페닐}-3-(트리플루오로메틸)벤젠술폰아미드 히드로클로라이드, N- {4- (1,4-diazepane-1-yl) -2-[(methylsulfonyl) amino] phenyl} -3- (trifluoromethyl) benzenesulfonamide hydrochloride, N-{4-(1,4-디아제판-1-일)-2-[(메틸술포닐)아미노]페닐}-2-메틸벤젠술폰아미드 히드로클로라이드, N- {4- (1,4-diazepane-1-yl) -2-[(methylsulfonyl) amino] phenyl} -2-methylbenzenesulfonamide hydrochloride, N-{4-(1,4-디아제판-1-일)-2-[(메틸술포닐)아미노]페닐}-4-(트리플루오로메톡시)벤젠술폰아미드 히드로클로라이드, N- {4- (1,4-diazepane-1-yl) -2-[(methylsulfonyl) amino] phenyl} -4- (trifluoromethoxy) benzenesulfonamide hydrochloride, N-{4-(1,4-디아제판-1-일)-2-[(메틸술포닐)아미노]페닐}-3,5-디메틸-4-이속사졸술폰아미드 히드로클로라이드, N- {4- (1,4-diazepane-1-yl) -2-[(methylsulfonyl) amino] phenyl} -3,5-dimethyl-4-isoxazolesulfonamide hydrochloride, N-{4-(1,4-디아제판-1-일)-2-[(메틸술포닐)아미노]페닐}-3-메톡시벤젠술폰아미드 히드로클로라이드, N- {4- (1,4-diazepane-1-yl) -2-[(methylsulfonyl) amino] phenyl} -3-methoxybenzenesulfonamide hydrochloride, N-{4-(1,4-디아제판-1-일)-2-[(메틸술포닐)아미노]페닐}-4-메틸벤젠술폰아미드 히드로클로라이드,N- {4- (1,4-diazepane-1-yl) -2-[(methylsulfonyl) amino] phenyl} -4-methylbenzenesulfonamide hydrochloride, N-{4-(1,4-디아제판-1-일)-2-[에틸(메틸술포닐)아미노]페닐}-4-메틸벤젠술폰아미드 히드로클로라이드, N- {4- (1,4-diazepane-1-yl) -2- [ethyl (methylsulfonyl) amino] phenyl} -4-methylbenzenesulfonamide hydrochloride, N-{4-(1,4-디아제판-1-일)-2-[에틸(메틸술포닐)아미노]페닐}-3,4-디메톡시벤젠술폰아미드 히드로클로라이드, N- {4- (1,4-diazepane-1-yl) -2- [ethyl (methylsulfonyl) amino] phenyl} -3,4-dimethoxybenzenesulfonamide hydrochloride, N-{4-(1,4-디아제판-1-일)-2-[에틸(메틸술포닐)아미노]페닐}-7-퀴놀린술폰아미드 히드로클로라이드, N- {4- (1,4-diazepane-1-yl) -2- [ethyl (methylsulfonyl) amino] phenyl} -7-quinolinesulfonamide hydrochloride, N-{4-(1,4-디아제판-1-일)-2-[메틸(메틸술포닐)아미노]페닐}-4-메틸벤젠술폰아미드 히드로클로라이드, N- {4- (1,4-diazepane-1-yl) -2- [methyl (methylsulfonyl) amino] phenyl} -4-methylbenzenesulfonamide hydrochloride, N-{4-(1,4-디아제판-1-일)-2-[메틸(메틸술포닐)아미노]페닐}-1-나프탈렌술폰아미드 히드로클로라이드, N- {4- (1,4-diazepane-1-yl) -2- [methyl (methylsulfonyl) amino] phenyl} -1-naphthalenesulfonamide hydrochloride, N-{4-(1,4-디아제판-1-일)-2-[메틸(메틸술포닐)아미노]페닐}-5-(2-피리디닐) -2-티오펜술폰아미드 히드로클로라이드, N- {4- (1,4-diazepane-1-yl) -2- [methyl (methylsulfonyl) amino] phenyl} -5- (2-pyridinyl) -2-thiophensulfonamide hydrochloride, N-{4-(1,4-디아제판-1-일)-2-[(페닐술포닐)아미노]페닐}-1-나프탈렌술폰아미드 히드로클로라이드, N- {4- (1,4-diazepane-1-yl) -2-[(phenylsulfonyl) amino] phenyl} -1-naphthalenesulfonamide hydrochloride, N-{4-(1,4-디아제판-1-일)-2-[(페닐술포닐)아미노]페닐}-5-(디메틸아미노)-1-나프탈렌술폰아미드 히드로클로라이드, N- {4- (1,4-diazepane-1-yl) -2-[(phenylsulfonyl) amino] phenyl} -5- (dimethylamino) -1-naphthalenesulfonamide hydrochloride, N-{4-(1,4-디아제판-1-일)-2-[(페닐술포닐)아미노]페닐}-8-퀴놀린술폰아미드 히드로클로라이드, N- {4- (1,4-diazepane-1-yl) -2-[(phenylsulfonyl) amino] phenyl} -8-quinolinesulfonamide hydrochloride, N-{4-(1,4-디아제판-1-일)-2-[(페닐술포닐)아미노]페닐}-2,4,6-트리메틸벤젠술폰아미드 히드로클로라이드, N- {4- (1,4-diazepane-1-yl) -2-[(phenylsulfonyl) amino] phenyl} -2,4,6-trimethylbenzenesulfonamide hydrochloride, N-{4-(1,4-디아제판-1-일)-2-[(페닐술포닐)아미노]페닐}-4-메틸벤젠술폰아미드 히드로클로라이드, N- {4- (1,4-diazepane-1-yl) -2-[(phenylsulfonyl) amino] phenyl} -4-methylbenzenesulfonamide hydrochloride, N-[5-(1,4-디아제판-1-일)-2-({[(E)-2-페닐에테닐]술포닐}아미노)페닐]벤젠술폰아미드 히드로클로라이드, N- [5- (1,4-diazepane-1-yl) -2-({[(E) -2-phenylethenyl] sulfonyl} amino) phenyl] benzenesulfonamide hydrochloride, N-{4-(1,4-디아제판-1-일)-2-[(페닐술포닐)아미노]페닐}-2,5-디메톡시벤젠술폰아미드 히드로클로라이드, N- {4- (1,4-diazepane-1-yl) -2-[(phenylsulfonyl) amino] phenyl} -2,5-dimethoxybenzenesulfonamide hydrochloride, N-{4-(1,4-디아제판-1-일)-2-[(페닐술포닐)아미노]페닐}-2-메틸벤젠술폰아미드 히드로클로라이드, N- {4- (1,4-diazepane-1-yl) -2-[(phenylsulfonyl) amino] phenyl} -2-methylbenzenesulfonamide hydrochloride, 4-부톡시-N-{4-(1,4-디아제판-1-일)-2-[(페닐술포닐)아미노]페닐}벤젠술폰아미드 히드로클로라이드, 4-butoxy-N- {4- (1,4-diazepane-1-yl) -2-[(phenylsulfonyl) amino] phenyl} benzenesulfonamide hydrochloride, N-{4-(1,4-디아제판-1-일)-2-[(페닐술포닐)아미노]페닐}-3,5-디메틸-4-이속사졸술폰아미드 히드로클로라이드, N- {4- (1,4-diazepane-1-yl) -2-[(phenylsulfonyl) amino] phenyl} -3,5-dimethyl-4-isoxazolesulfonamide hydrochloride, N-{4-(1,4-디아제판-1-일)-2-[(페닐술포닐)아미노]페닐}-5-플루오로-2-메틸벤젠술폰아미드 히드로클로라이드, N- {4- (1,4-diazepane-1-yl) -2-[(phenylsulfonyl) amino] phenyl} -5-fluoro-2-methylbenzenesulfonamide hydrochloride, N-{4-(1,4-디아제판-1-일)-2-[(페닐술포닐)아미노]페닐}-4-(메틸술포닐)벤젠술폰아미드 히드로클로라이드, N- {4- (1,4-diazepane-1-yl) -2-[(phenylsulfonyl) amino] phenyl} -4- (methylsulfonyl) benzenesulfonamide hydrochloride, N-{4-(1,4-디아제판-1-일)-2-[(메틸술포닐)아미노]페닐}-N-메틸벤젠술폰아미드 히드로클로라이드, N- {4- (1,4-diazepane-1-yl) -2-[(methylsulfonyl) amino] phenyl} -N-methylbenzenesulfonamide hydrochloride, N-{5-(1,4-디아제판-1-일)-2-[메틸(페닐술포닐)아미노]페닐}-4-메틸벤젠술폰아미드 히드로클로라이드, N- {5- (1,4-diazepane-1-yl) -2- [methyl (phenylsulfonyl) amino] phenyl} -4-methylbenzenesulfonamide hydrochloride, 3-아미노-4-(1,4-디아제판-1-일)-N-(4-메톡시페닐)벤젠술폰아미드 히드로클로라이드, 3-amino-4- (1,4-diazepane-1-yl) -N- (4-methoxyphenyl) benzenesulfonamide hydrochloride, 3-아미노-4-(1,4-디아제판-1-일)-N-(3-메톡시페닐)벤젠술폰아미드 히드로클로라이드, 3-amino-4- (1,4-diazepane-1-yl) -N- (3-methoxyphenyl) benzenesulfonamide hydrochloride, 3-아미노-4-(1,4-디아제판-1-일)-N-(2-메톡시페닐)벤젠술폰아미드 히드로클로라이드, 3-amino-4- (1,4-diazepane-1-yl) -N- (2-methoxyphenyl) benzenesulfonamide hydrochloride, 3-아미노-4-(1,4-디아제판-1-일)-N-(3-플루오로페닐)벤젠술폰아미드 히드로클로라이드, 3-amino-4- (1,4-diazepane-1-yl) -N- (3-fluorophenyl) benzenesulfonamide hydrochloride, 3-아미노-4-(1,4-디아제판-1-일)-N-메틸-N-페닐벤젠술폰아미드 히드로클로라이드, 3-amino-4- (1,4-diazepane-1-yl) -N-methyl-N-phenylbenzenesulfonamide hydrochloride, 3-아미노-4-(1,4-디아제판-1-일)-N-(4-이소프로필페닐)벤젠술폰아미드 히드로클로라이드, 3-amino-4- (1,4-diazepan-1-yl) -N- (4-isopropylphenyl) benzenesulfonamide hydrochloride, 3-아미노-4-(1,4-디아제판-1-일)-N-(4-메틸페닐)벤젠술폰아미드 히드로클로라이드, 3-amino-4- (1,4-diazepane-1-yl) -N- (4-methylphenyl) benzenesulfonamide hydrochloride, 3-아미노-4-(1,4-디아제판-1-일)-N-(2,5-디메틸페닐)벤젠술폰아미드 히드로클로라이드, 3-amino-4- (1,4-diazepane-1-yl) -N- (2,5-dimethylphenyl) benzenesulfonamide hydrochloride, 3-아미노-N-(3-클로로페닐)-4-(1,4-디아제판-1-일)벤젠술폰아미드 히드로클로라이드, 3-amino-N- (3-chlorophenyl) -4- (1,4-diazepan-1-yl) benzenesulfonamide hydrochloride, 3-아미노-N-(2-클로로페닐)-4-(1,4-디아제판-1-일)벤젠술폰아미드 히드로클로라이드, 3-amino-N- (2-chlorophenyl) -4- (1,4-diazepan-1-yl) benzenesulfonamide hydrochloride, 3-아미노-N-(2,4-디클로로페닐)-4-(1,4-디아제판-1-일)벤젠술폰아미드 히드로클로라이드, 3-amino-N- (2,4-dichlorophenyl) -4- (1,4-diazepan-1-yl) benzenesulfonamide hydrochloride, 3-아미노-N-(2-메틸-5-클로로-페닐)-4-(1,4-디아제판-1-일)벤젠술폰아미드 히드로클로라이드, 3-amino-N- (2-methyl-5-chloro-phenyl) -4- (1,4-diazepane-1-yl) benzenesulfonamide hydrochloride, 3-아미노-N-(2-메틸-3-클로로-페닐)-4-(1,4-디아제판-1-일)벤젠술폰아미드 히드로클로라이드, 3-amino-N- (2-methyl-3-chloro-phenyl) -4- (1,4-diazepane-1-yl) benzenesulfonamide hydrochloride, 3-아미노-N-(4-트리플루오로-페닐)-4-(1,4-디아제판-1-일)벤젠술폰아미드 히드로클로라이드, 3-amino-N- (4-trifluoro-phenyl) -4- (1,4-diazepan-1-yl) benzenesulfonamide hydrochloride, 3-아미노-N-(4-플루오로페닐)-4-(1,4-디아제판-1-일)벤젠술폰아미드 히드로클로라이드, 3-amino-N- (4-fluorophenyl) -4- (1,4-diazepan-1-yl) benzenesulfonamide hydrochloride, 3-아미노-N-(2-플루오로페닐)-4-(1,4-디아제판-1-일)벤젠술폰아미드 히드로클로라이드, 3-amino-N- (2-fluorophenyl) -4- (1,4-diazepan-1-yl) benzenesulfonamide hydrochloride, 3-아미노-4-(4-메틸-1,4-디아제판-1-일)-N-페닐벤젠술폰아미드 히드로클로라이드, 3-amino-4- (4-methyl-1,4-diazepan-1-yl) -N-phenylbenzenesulfonamide hydrochloride, 3-아미노-4-(1,4-디아제판-1-일)-N-페닐벤젠술폰아미드 히드로클로라이드, 3-amino-4- (1,4-diazepan-1-yl) -N-phenylbenzenesulfonamide hydrochloride, 2-(1,4-디아제판-1-일)-5-(4-모르폴리닐술포닐)페닐아민 히드로클로라이드,2- (1,4-diazepan-1-yl) -5- (4-morpholinylsulfonyl) phenylamine hydrochloride, 4-(1,4-디아제판-1-일)-N-페닐-3-[(페닐술포닐)아미노]벤젠술폰아미드 히드로클로라이드, 4- (1,4-diazepane-1-yl) -N-phenyl-3-[(phenylsulfonyl) amino] benzenesulfonamide hydrochloride, 4-(1,4-디아제판-1-일)-N-페닐-3-[(메틸술포닐)아미노]벤젠술폰아미드 히드로클로라이드, 4- (1,4-diazepane-1-yl) -N-phenyl-3-[(methylsulfonyl) amino] benzenesulfonamide hydrochloride, 3-아미노-N-(3-클로로페닐)-4-(4-메틸-1-피페라지닐)벤젠술폰아미드 히드로클로라이드, 3-amino-N- (3-chlorophenyl) -4- (4-methyl-1-piperazinyl) benzenesulfonamide hydrochloride, 3-아미노-N-(2-메톡시페닐)-4-(4-메틸-1-피페라지닐)벤젠술폰아미드 히드로클로라이드, 3-amino-N- (2-methoxyphenyl) -4- (4-methyl-1-piperazinyl) benzenesulfonamide hydrochloride, 3-아미노-N-(2-메톡시페닐)-4-(1-피페라지닐)벤젠술폰아미드 히드로클로라이드, 3-amino-N- (2-methoxyphenyl) -4- (1-piperazinyl) benzenesulfonamide hydrochloride, 3-아미노-N-(2-메톡시페닐)-4-(3-메틸-1-피페라지닐)벤젠술폰아미드 히드로클로라이드, 3-amino-N- (2-methoxyphenyl) -4- (3-methyl-1-piperazinyl) benzenesulfonamide hydrochloride, 3-아미노-4-(헥사히드로-피롤로[1,2-a]피라진-2-일)-N-(2-메톡시페닐)벤젠술폰아미드 히드로클로라이드, 3-amino-4- (hexahydro-pyrrolo [1,2-a] pyrazin-2-yl) -N- (2-methoxyphenyl) benzenesulfonamide hydrochloride, 3-아미노-N-페닐-4-피페라진-1-일-벤젠술폰아미드 히드로클로라이드, 3-amino-N-phenyl-4-piperazin-1-yl-benzenesulfonamide hydrochloride, 3-아미노-4-(3-메틸-피페라진-1-일)-N-페닐-벤젠술폰아미드 히드로클로라이드, 3-amino-4- (3-methyl-piperazin-1-yl) -N-phenyl-benzenesulfonamide hydrochloride, 3-아미노-4-(4-에틸-피페라진-1-일)-N-페닐-벤젠술폰아미드 히드로클로라이드, 3-amino-4- (4-ethyl-piperazin-1-yl) -N-phenyl-benzenesulfonamide hydrochloride, 3-아미노-4-(헥사히드로피롤로[1,2-a]피라진-1-일)-N-페닐-벤젠술폰아미드 히드로클로라이드, 3-amino-4- (hexahydropyrrolo [1,2-a] pyrazin-1-yl) -N-phenyl-benzenesulfonamide hydrochloride, 3-아미노-4-(5-메틸-2,5-디아자-비시클로[2.2.1]헵트-2-일)-N-페닐-벤젠술폰아미드 히드로클로라이드, 3-amino-4- (5-methyl-2,5-diaza-bicyclo [2.2.1] hept-2-yl) -N-phenyl-benzenesulfonamide hydrochloride, 3-아미노-4-(트란스-2,5-디메틸-피페라진-1-일)-N-(2-메톡시-페닐)벤젠술폰아미드 히드로클로라이드,3-amino-4- (trans-2,5-dimethyl-piperazin-1-yl) -N- (2-methoxy-phenyl) benzenesulfonamide hydrochloride, 2-(3-아미노-4-[1,4]디아제판-1-일-벤젠술포닐)-벤즈아미드 디아세트산,2- (3-amino-4- [1,4] diazepan-1-yl-benzenesulfonyl) -benzamide diacetic acid, 4-[4-(3-플루오로-2-메톡시-페닐술파모일)-2-아미노-페닐]-[1,4]디아제판 디트리플루오로아세트산, 4- [4- (3-fluoro-2-methoxy-phenylsulfamoyl) -2-amino-phenyl]-[1,4] diazepane ditrifluoroacetic acid, 2-[1,4]디아제판-1-일-5-(3,4-디히드로-1H-이소퀴놀린-2-술포닐)-아닐린 디히드로클로라이드, 2- [1,4] diazepan-1-yl-5- (3,4-dihydro-1H-isoquinoline-2-sulfonyl) -aniline dihydrochloride, 4-[4-(3,4-디히드로-2H-퀴놀린-1-술포닐)-2-아미노-페닐]-[1,4]디아제판 디플루오로아세트산, 4- [4- (3,4-dihydro-2H-quinoline-1-sulfonyl) -2-amino-phenyl]-[1,4] diazepane difluoroacetic acid, 3-아미노-2-클로로-N-나프탈렌-1-일-4-피페라진-1-일-벤젠술폰아미드 히드로클로라이드.3-Amino-2-chloro-N-naphthalen-1-yl-4-piperazin-1-yl-benzenesulfonamide hydrochloride. 하기 단계를 포함하는, 제 1 항 또는 제 2 항에 따른 화합물의 제조 방법:A process for preparing a compound according to claim 1, comprising the following steps: (a) 마일드 (mild) 한 염기성 조건 하에 시클릭 디아민을 할로겐 및 니트로 치환 벤젠에 도입하는 단계; (a) introducing cyclic diamine to halogen and nitro substituted benzene under mild basic conditions; (b) 니트로를 상응하는 아민으로 환원하는 단계; (b) reducing nitro to the corresponding amine; (c) 술포닐클로라이드에 의한 아민의 대칭형 또는 비대칭형 술포닐화 단계;(c) symmetric or asymmetric sulfonylation of the amine with sulfonylchloride; (d) 염기성 조건에서의 알킬화에 의한 기 R3 및 R4 의 도입 단계.(d) introduction of groups R 3 and R 4 by alkylation at basic conditions. 약제학적으로 허용되는 희석제 또는 담체와 배합된, 활성 성분으로서의 제 1 항 또는 제 2 항에 따른 화합물을 함유하는 약제학적 제형물. A pharmaceutical formulation containing a compound according to claim 1 or 2 as an active ingredient in combination with a pharmaceutically acceptable diluent or carrier. 삭제delete 유효량의 제 1 항 또는 제 2 항에 따른 화합물을 5-HT6 수용체 활성 조절이 필요한 포유류에게 투여하는 것을 포함하는, 비만 또는 제 II 형 당뇨병의 치료 또는 예방을 위한 5-HT6 수용체 활성을 조절하기 위한 약제학적 제형물. Adjusting the claims 1 or 5-HT 6 receptor activity for obesity or the treatment or prevention of type II diabetes, comprising administering a compound according to 2, wherein to a mammal requiring 5-HT 6 receptor activity modulation of an effective amount of Pharmaceutical formulations for 제 1 항 또는 제 2 항에 있어서, 비만, 제 II 형 당뇨병, 또는 비만 및 제 II 형 당뇨병의 치료용인 화합물.A compound according to claim 1 or 2 for the treatment of obesity, type II diabetes, or obesity and type II diabetes. 비만, 제 II 형 당뇨병, 또는 비만 및 제 II 형 당뇨병의 치료 또는 예방용 의약의 제조를 위한 제 1 항 또는 제 2 항에 따른 화합물의 사용 방법. Use of a compound according to claim 1 or 2 for the manufacture of a medicament for the treatment or prophylaxis of obesity, type II diabetes, or obesity and type II diabetes. 비만, 제 II 형 당뇨병, 또는 비만 및 제 II 형 당뇨병의 치료 또는 예방용의 약제학적 제형물로서, 활성 성분이 제 1 항 또는 제 2 항에 따른 화합물인 약제학적 제형물. A pharmaceutical formulation for the treatment or prevention of obesity, type II diabetes, or obesity and type II diabetes, wherein the active ingredient is a compound according to claim 1. 삭제delete 삭제delete 삭제delete 하기의 단계를 포함하는, 화학식 II 의 화합물 또는 약제학적으로 허용되는 그의 염의 제조 방법A process for preparing a compound of formula (II) or a pharmaceutically acceptable salt thereof, comprising the following steps [화학식 II][Formula II]
Figure 712009003396831-pct00185
Figure 712009003396831-pct00185
 [식 중, [In the meal, R9, R12 및 R14 는 H 이거나; 또는R 9 , R 12 and R 14 are H; or R9, R12 및 R14 중 2 개가 H 이며; 남는 R9, R12 및 R14 는 Two of R 9 , R 12 and R 14 are H; The remaining R 9 , R 12 and R 14 (a) -NH2, (a) -NH 2 , (b) -NHR6, (b) -NHR 6 , (c) -NR6R7, (c) -NR 6 R 7 , (d) -N(CO)R6,(d) -N (CO) R 6 , (e) -N(CS)R6 또는 (e) -N (CS) R 6 or (f) -NO2 이며;(f) -NO 2 ; R10 은 제 1 항에서의 화학식 I 에서 정의된 기 R3 이며; R 10 is a group R 3 as defined in formula I in claim 1; R11 은 제 1 항에서의 화학식 I 에서 정의된 기 R1 이며; R 11 is a group R 1 as defined in formula I in claim 1 ; R13 은R 13 is (a) 호모피페라진, (a) homopiperazine, (b) 메틸호모피페라진, 또는(b) methyl homopiperazine, or (c) 제 1 항에서의 화학식 I 에서 정의된 기 R5 이며, 여기서 R8 은 제 1 항에서의 화학식 I 에서와 같이 정의되며; (c) a group R 5 as defined in formula I in claim 1, wherein R 8 is defined as in formula I in claim 1; Y 는 제 1 항에서의 화학식 I 에서와 같이 정의되며, Y is defined as in formula I in claim 1, 각각의 R6 및 R7 은 독립적으로 제 1 항에서의 화학식 I 에서와 같이 정의된다]:Each of R 6 and R 7 is independently defined as in formula I in claim 1; (a) 마일드한 염기성 조건 하에 시클릭 디아민을 할로겐 및 니트로 치환 벤젠에 도입하는 단계; (a) introducing cyclic diamine to halogen and nitro substituted benzene under mild basic conditions; (b) 니트로를 상응하는 아민으로 환원하는 단계; (b) reducing nitro to the corresponding amine; (c) 아민과 술포닐클로라이드의 반응에 의한 술포닐아미드기의 선택적인 도입 단계;(c) selective introduction of sulfonylamide groups by reaction of amines with sulfonylchlorides; (d) 방향족 친핵성 치환에 의한 술포닐아미노기의 도입 단계.(d) introducing a sulfonylamino group by aromatic nucleophilic substitution. 삭제delete 삭제delete 삭제delete 삭제delete 삭제delete 삭제delete 삭제delete 삭제delete
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SE0101659-1 2001-05-11
US29410201P 2001-05-29 2001-05-29
US29413201P 2001-05-29 2001-05-29
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US60/294,132 2001-05-29
SE0101958A SE0101958D0 (en) 2001-06-05 2001-06-05 New compounds
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998027081A1 (en) * 1996-12-19 1998-06-25 Smithkline Beecham Plc Sulphonamide derivatives, process for their preparation, and their use as medicaments
WO2001016096A2 (en) * 1999-09-01 2001-03-08 Aventis Pharma Deutschland Gmbh Use of bis-sulfonamides for producing medicaments used for preventing or treating hyperlipidaemia

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998027081A1 (en) * 1996-12-19 1998-06-25 Smithkline Beecham Plc Sulphonamide derivatives, process for their preparation, and their use as medicaments
WO2001016096A2 (en) * 1999-09-01 2001-03-08 Aventis Pharma Deutschland Gmbh Use of bis-sulfonamides for producing medicaments used for preventing or treating hyperlipidaemia

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