KR20020015379A - Method for treating chronic pain using mek inhibitors - Google Patents

Method for treating chronic pain using mek inhibitors Download PDF

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KR20020015379A
KR20020015379A KR1020027000665A KR20027000665A KR20020015379A KR 20020015379 A KR20020015379 A KR 20020015379A KR 1020027000665 A KR1020027000665 A KR 1020027000665A KR 20027000665 A KR20027000665 A KR 20027000665A KR 20020015379 A KR20020015379 A KR 20020015379A
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methyl
phenyl
iodo
phenylamino
fluoro
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베렛트스티븐더글라스
브릿지스알렉산더제임스
테클헤일
딕손앨리스테어
리케빈
피녹로버트덴햄
장루-얀
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로즈 암스트롱, 크리스틴 에이. 트러트웨인
워너-램버트 캄파니
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Abstract

본 발명은 청구의 범위 제 1 항의 하기 화학식 I에 개시된 디아릴아민을 사용하는 만성 동통의 치료방법에 관한 것이다:The present invention relates to a method of treating chronic pain using a diarylamine as described in claim 1 of claim 1:

화학식 IFormula I

Description

엠이케이 억제제를 사용하는 만성 동통의 치료방법{METHOD FOR TREATING CHRONIC PAIN USING MEK INHIBITORS}[0001] METHOD FOR TREATING CHRONIC PAIN USING MEK INHIBITORS [0002]

신경 경로중 임의의 곳에서의 이상은 신경 신호를 파괴하며, 또다시 뇌속에서 비정상적으로 해석되어 신경병증성 동통을 초래하게 된다. 신경병증성 동통으로는 예컨대 심한 두통, 작열감 또는 접촉에 대한 과민증이 있을 수 있다. 신경병증성 동통과 관련된 질환 또는 증상으로는 당뇨병성 신경병증, 작열통(causalgia), 플렉서스 어벌젼(plexus avulsion), 신경종, 혈관염, 압궤 손상(crushing injury), 바이러스 감염(예: 포진 바이러스 감염 또는 HIV), 수축 손상(constriction injury), 조직 손상, 말초 신경계로부터 중추 신경계까지의 신경 손상, 사지 절단, 갑상선기능저하증(hypothyroidism), 요독증(uremia), 만성 알콜중독증, 수술후 동통(post-operative pain), 관절염, 배통(back pain) 및 비타민 결핍증이 포함되되이에 한정되지 않는다.Any abnormality in the nerve pathway destroys the nerve signal, and is again interpreted abnormally in the brain, resulting in neuropathic pain. Neuropathic pain can include, for example, severe headache, burning sensation or hypersensitivity to contact. Diseases or conditions associated with neuropathic pain include, but are not limited to, diabetic neuropathy, causalgia, plexus avulsion, neuroma, vasculitis, crushing injury, viral infection (e.g., HIV, constriction injury, tissue damage, nerve damage from the peripheral nervous system to the central nervous system, limb amputation, hypothyroidism, uremia, chronic alcoholism, post-operative pain, , Arthritis, back pain, and vitamin deficiencies.

대상포진(herpes zoster(shingles))과 같은 감염은 신경 염증을 야기하고, 바이러스 감염 부위에 국부화된 만성 작열인 포진후 신경통(postherpetic neuralgia)을 생성시킬 수 있다. 통각과민(hyperalgesia)은 이전의 독성 자극이 더욱더 고통스러워지는 경우를 지칭하며, 무해자극통증(allodynia)은 이전의 비독성 자극(예컨대, 옷감의 접촉 또는 산들바람)이 더욱 고통스러워지는 경우를 지칭한다. 반사성 교감신경 영양장애(reflex sympathetic dystrophy)는 종창(swelling) 및 발한, 또는 국부 혈류의 변화, 조직 위축 또는 골다공증을 수반한다. 작열통(이는 심한 작열 동통 및 종창을 포함함), 발한 및 혈류의 변화는 좌골 신경과 같은 주요 신경의 손상 또는 질환에 수반될 수도 있다. 몇몇 유형의 만성 하부 배통은 신경병증성 요소(예컨대, 좌골신경통, 척수회백질염후 (postpoliomyelitis) 및 CPRM)를 가질 수 있다. 신경병증성 동통은 또한 암 또는 화학요법에 의해 유발될 수 있다.Infection, such as herpes zoster (shingles), can cause neuroinflammation and produce postherpetic neuralgia, a chronic scree that localizes to the site of viral infection. Hyperalgesia refers to cases where previous toxic stimuli become more painful and allodynia refers to cases where previous non-toxic stimuli (such as contact or breeze of cloth) become more painful do. Reflex sympathetic dystrophy involves swelling and sweating, or changes in local blood flow, tissue atrophy or osteoporosis. Alterations in inflammatory markers (including severe scarring and swelling), sweating and blood flow may be associated with injury or disease of the major nerves, such as the sciatic nerve. Some types of chronic lower back pain may have neuropathic components (e.g., sciatica, spinal fluid postpoliomyelitis, and CPRM). Neuropathic pain can also be caused by cancer or chemotherapy.

신경병증성 동통은 현재 항경련제(예: 카바마제핀) 및 항우울제(예: 아미트립탈린)를 사용하여 치료되고 있다. NSAIDS 및 아편양제제(opioid)는 일반적으로 거의 효과가 없다[문헌 "Fields et al 1994 Textbook of Pain p 991-996(pub: Churchill Livingstone), James & Page 1994 J. Am. Pediatr. Med. Assoc, 8: 439-447, Galer, 1995 Neurology 45 S17-S25"]. 가바펜틴(gabapentin)으로 치료되어 온 신경병증 증상으로는 포진후 신경통, 척수회백질염후, CPRM, HIV-관련 신경병증, 삼차신경통(trigeminal neuralgia) 및 반사성 교감신경 영양장애(RSD)가 포함된다. 소염제의 일반적인 약한 효능은 만성 동통에 관한 메커니즘이 통각과민과 구분된다는 것을 암시한다.Neuropathic pain is currently being treated with anticonvulsants (eg, carbamazepine) and antidepressants (eg, amitriptyline). NSAIDS and opioids generally have little effect [Fields et al 1994 Textbook of Pain 991-996 (pub: Churchill Livingstone), James & J. Am. Pediatr Med. Assoc, 8: 439-447, Galer, 1995 Neurology 45 S17-S25 "]. Neuropathic symptoms that have been treated with gabapentin include postherpetic neuralgia, spinal cord colorectal cancer, CPRM, HIV-related neuropathy, trigeminal neuralgia, and reflex sympathetic dystrophy (RSD). The general weak efficacy of anti-inflammatory drugs suggests that the mechanism of chronic pain is distinct from hyperalgesia.

발명의 요약SUMMARY OF THE INVENTION

본 발명은 만성 동통을 치료하는 방법에 관한 것이며, 이 방법은 MEK 억제제를 포함하는 조성물을 이러한 치료가 필요한 환자에게 투여하는 단계를 포함하고 있다. 만성 동통으로는 신경병증성 동통, 특발성 동통, 및 비타민 결핍, 요독증, 갑상선기능저하, 수술후 동통, 관절염, 배통 및 만성 알콜중독증과 관련된 동통이 포함된다. 본 발명은 또한 만성 동통의 치료를 위해 배합되는 개시된 바와 같은 조성물에 관한 것이다. 이러한 조성물은 1999년 12월 21일자로 국제출원된 특허출원 PCT/US99/30416 호에 개시된 구조를 갖는 하나 이상의 MEK 억제제 화합물을 포함할 수 있다.The present invention relates to a method of treating chronic pain comprising administering to a patient in need of such treatment a composition comprising a MEK inhibitor. Chronic pain includes neuropathic pain, idiopathic pain, and pain associated with vitamin deficiency, uremia, hypothyroidism, postoperative pain, arthritis, back pain, and chronic alcoholism. The present invention also relates to a composition as disclosed, which is formulated for the treatment of chronic pain. Such a composition may comprise one or more MEK inhibitor compounds having the structure disclosed in International Patent Application No. PCT / US99 / 30416, filed December 21, 1999.

MEK 억제제의 예로는 하기 화학식 I을 갖는 화합물이 포함된다:Examples of MEK inhibitors include compounds having the formula < RTI ID = 0.0 > (I) <

상기 식에서,In this formula,

W는 식W represents the formula

중 하나이고,/ RTI >

X1은 O, S 또는 NRF이고, X2는 OH, SH 또는 NHRE이되, 여기서 RE및 RF는 각각 H 또는 C1-4알킬이고,X 1 is O, S or NR F and X 2 is OH, SH or NHR E , wherein R E and R F are each H or C 1-4 alkyl,

R1및 R2는 각각 H, F, NO2, Br 및 Cl로부터 독립적으로 선택되고, R1은 또한 SO2NRGRH일 수 있거나, 또는 R1및 R2는 이들이 결합된 벤젠 고리와 함께 인돌, 이소인돌, 벤조푸란, 벤조티오펜, 인다졸, 벤즈이미다졸 또는 벤즈티오아졸을 구성하고,R 1 and R 2 are each independently selected from H, F, NO 2 , Br and Cl, and R 1 may also be SO 2 NR G R H , or R 1 and R 2 may be a benzene ring, Together form indole, isoindole, benzofuran, benzothiophene, indazole, benzimidazole or benzthioazole,

R3은 H 및 F로부터 선택되고,R < 3 > is selected from H and F,

RG, RH및 R4는 각각 H, Cl 및 CH3으로부터 독립적으로 선택되고,R G , R H and R 4 are each independently selected from H, Cl and CH 3 ,

R5는 H 또는 C1-4알킬이되, 여기서R 5 is H or C 1-4 alkyl, wherein

상기 탄화수소 라디칼은 각각 할로, 하이드록실, 아미노, (아미노)설포닐 및 NO2로부터 독립적으로 선택된 1 내지 3개의 치환기로 선택적으로 치환되고,Wherein said hydrocarbon radicals are each optionally substituted with 1 to 3 substituents independently selected from halo, hydroxyl, amino, (amino) sulfonyl and NO 2 ,

상기 헤테로사이클릭 라디칼은 각각 할로, C1-4알킬, C3-6사이클로알킬, C3-4알케닐, C3-4알키닐, 페닐, 하이드록실, 아미노, (아미노)설포닐 및 NO2로부터 독립적으로 선택된 1 내지 3개의 치환기로 선택적으로 치환되며, 여기서 상기 치환기 알킬, 사이클로알킬, 알케닐, 알키닐 또는 페닐은 각각 또다시 할로, C1-2알킬, 하이드록실, 아미노 및 NO2로부터 독립적으로 선택된 1 또는 2개의 치환기로 선택적으로 치환된다.Wherein said heterocyclic radical is selected from the group consisting of halo, C 1-4 alkyl, C 3-6 cycloalkyl, C 3-4 alkenyl, C 3-4 alkynyl, phenyl, hydroxyl, amino, (amino) 2 independently are optionally substituted by 1 to 3 substituents selected, where the substituents alkyl, cycloalkyl, alkenyl, alkynyl or phenyl is again halo, C 1-2 alkyl, hydroxyl, amino, and NO 2 from each Lt; RTI ID = 0.0 > 1 < / RTI >

본 발명은 또한 개시된 화합물의 약학적으로 허용가능한 염 또는 개시된 화합물의 C1-8에스테르에 관한 것이다. 예를 들면, 개시된 알콜 화합물은 하이드록실기의 H를 -C(=O)C1-7아실기로 치환시켜 수득된 구조를 갖는 에스테르를 형성할 수 있다.The present invention also relates to pharmaceutically acceptable salts of the disclosed compounds or C 1-8 esters of the disclosed compounds. For example, the disclosed alcohol compound can form an ester having a structure obtained by substituting H in the hydroxyl group with a -C (= O) C 1-7 acyl group.

본 발명의 바람직한 양태는 하기 화합물중 하나 이상을 사용하는 방법을 포함한다:Preferred embodiments of the invention include methods using one or more of the following compounds:

(a) 2,4-비스-(2-클로로-4-요오도-페닐아미노)-3-플루오로-5-니트로-벤조산, 5-[3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-[1,3,4]옥사디아졸-2-일아민, 5-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-[1,3,4]옥사디아졸-2-올, (2,3-디플루오로-6-[1,3,4]옥사디아졸-2-일-페닐)-(4-요오도-2-메틸-페닐)-아민, 5-[3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-[1,3,4]옥사디아졸-2-티올, 5-[3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-4H-[1,2,4]트리아졸-3-일아민, 및 5-[3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-4H-[1,2,4]트리아졸-3-티올로부터 선택된 구조를 갖는 상기 MEK 억제제; 및(a) 2,4-Bis- (2-chloro-4-iodo-phenylamino) -3-fluoro-5-nitro- Methyl-phenylamino) -phenyl] - [1,3,4] oxadiazol-2-ylamine, 5- [4-fluoro-2- (4- Phenyl] - [1,3,4] oxadiazol-2-ol, (2,3-difluoro-6- [1,3,4] oxadiazol- - (4-iodo-2-methyl-phenyl) -amine, 5- [3,4-difluoro-2- , 4] oxadiazole-2-thiol, 5- [3,4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -4 H - [1,2,4 ] triazol-3-ylamine, and 5- [3,4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -4 H - [1,2,4] Triazole-3-thiol; And

(b) 2,4-비스-(2-클로로-4-요오도-페닐아미노)-3-플루오로-5-니트로-벤조산 구조를 갖는 상기 MEK 억제제.(b) said MEK inhibitor having a 2,4-bis- (2-chloro-4-iodo-phenylamino) -3-fluoro-5-nitro-benzoic acid structure.

본 발명의 다른 양태는 하기 발명의 상세한 설명, 실시예 및 청구의 범위에서 제시된다.Other aspects of the invention are set forth in the following description, examples and claims.

본 발명은 MEK 억제제를 사용하는 만성 동통의 치료방법에 관한 것이다. 만성 동통으로는 신경병증성 동통(neuropathic pain) 및 만성 염증성 동통이 포함된다.The present invention relates to a method of treating chronic pain using a MEK inhibitor. Chronic pain includes neuropathic pain and chronic inflammatory pain.

도 1은 시간(일)의 함수로서 발 도피 역치(paw withdrawal threshold, PWT)(g)를 도시하는 막대 그래프이다. 빈 막대, 교차-평행선 막대 및 단일-평행선 막대는 각각 비히클, PD 198306 및 프레가발린(pregabalin)이다. 화살표는 약제 투여 시간(30㎎/㎏, 경구(p.o.) 투여)을 나타낸다.Figure 1 is a bar graph showing the paw withdrawal threshold (PWT) (g) as a function of time (days). The empty bars, the cross-parallel bars and the single-parallel bars are the vehicle, PD 198306 and pregabalin, respectively. The arrows indicate drug administration time (30 mg / kg, oral (p.o.) administration).

도 2는 시간(일)의 함수로서 폰 프레이 헤어 필라멘트(von Frey hair filament)를 사용하여 발 도피를 유발시키는데 필요한 힘(g)을 도시하는 막대 그래프이다. 기준선(BL)은 처리 전에 측정하였다. PD 198306(3 내지 30㎎/㎏) 또는 프레가발린(30㎎/㎏)의 단일 경구 투여된 동물의 도피 역치를 처리 1시간 후에 재검사하였다. 처리는 2일 동안 2회/일로 반복하였다. 결과는 평균 ±1st및 3rd사분값(四分値, quartile)으로 표기한다.*P＜0.05,**P＜0.01,***P＜0.001은 비히클-처리된 동물과 유의적으로 상이하다(만-휘트니(Mann-Whitney) t 시험; n = 7 내지 8).Figure 2 is a bar graph showing the force (g) required to induce foot escape using von Frey hair filaments as a function of time (days). The baseline (BL) was measured before treatment. The escape thresholds of single oral dosed animals of PD 198306 (3 to 30 mg / kg) or pregabalin (30 mg / kg) were re-examined 1 hour after treatment. Treatment was repeated twice / day for 2 days. Results are expressed as mean ± 1 st and 3 rd quartiles. * P <0.05, ** P <0.01, *** P <0.001 are significantly different from vehicle-treated animals (Mann-Whitney t test, n = 7 to 8).

도 3은 시간(일)의 함수로서 폰 프레이 헤어 필라멘트를 사용하여 발 도피를 유발시키는데 필요한 힘(g)을 도시하는 막대 그래프이다. 기준선(BL)은 처리 전에 측정하였다. PD 198306(3 내지 30㎎/㎏) 또는 프레가발린(30㎎/㎏)의 단일 경구 투여된 동물의 도피 역치를 처리 1시간 후에 재검사하였다. 처리는 2일 동안 2회/일로 반복하였다. 결과는 평균 ±1st및 3rd사분값으로 표기한다.**P＜0.01은 비히클-처리된 동물과 유의적으로 상이하다(만-휘트니 t 시험; n = 6).Fig. 3 is a bar graph showing the force (g) required to cause foot escape using the von Frey hair filament as a function of time (days). The baseline (BL) was measured before treatment. The escape thresholds of single oral dosed animals of PD 198306 (3 to 30 mg / kg) or pregabalin (30 mg / kg) were re-examined 1 hour after treatment. Treatment was repeated twice / day for 2 days. Results are expressed as mean ± 1 st and 3 rd quartiles. ** P &lt; 0.01 is significantly different from vehicle-treated animals (Bay-Whitney test, n = 6).

도 4는 시간(일)의 함수로서 폰 프레이 헤어 필라멘트를 사용하여 발 도피를 유발시키는데 필요한 힘(g)을 도시하는 막대 그래프이다. 기준선(BL)은 처리 전에 측정하였다. PD 198306(1 내지 30㎍/10㎕) 또는 프레가발린(100㎍/10㎕)의 단일 수막강내(i.t.) 투여된 동물의 도피 역치를 처리 30분, 1시간 및 2시간 후에 재검사하였다. 결과는 평균 ±1st및 3rd사분값으로 표기한다.*P＜0.05,***P＜0.001은 비히클-처리된 동물과 유의적으로 상이하다(만-휘트니 t 시험; n = 7 내지 9).Figure 4 is a bar graph showing the force (g) required to induce foot escape using a Von Frey hair filament as a function of time (days). The baseline (BL) was measured before treatment. The escape thresholds of animals treated with PD 198306 (1 to 30 μg / 10 μl) or pregabalin (100 μg / 10 μl) in a single cannula were resentuated at 30 minutes, 1 hour and 2 hours after treatment. Results are expressed as mean ± 1 st and 3 rd quartiles. * P &lt; 0.05, *** P &lt; 0.001 significantly different from vehicle-treated animals (only Whitney test; n = 7 to 9).

도 5는 시간(일)의 함수로서 폰 프레이 헤어 필라멘트를 사용하여 발 도피를 유발시키는데 필요한 힘(g)을 도시하는 막대 그래프이다. 기준선(BL)은 처리 전에측정하였다. PD 198306(1 내지 30㎍/10㎕) 또는 프레가발린(100㎍/10㎕)의 단일 수막강내 투여된 동물의 도피 역치를 처리 30분, 1시간 및 2시간 후에 재검사하였다. 결과는 평균 ±1st및 3rd사분값으로 표기한다.*P＜0.05,**P＜0.01,***P＜0.001은 비히클-처리된 동물과 유의적으로 상이하다(만-휘트니 t 시험; n = 6 내지 8).Figure 5 is a bar graph showing the force (g) required to induce foot escape using a Von Frey hair filament as a function of time (days). The baseline (BL) was measured before treatment. The escape thresholds of PD 198306 (1 to 30 μg / 10 μl) or pregabalin (100 μg / 10 μl) single-dose intratracheally administered animals were re-examined at 30 minutes, 1 hour and 2 hours after treatment. Results are expressed as mean ± 1 st and 3 rd quartiles. * P <0.05, ** P <0.01, *** P <0.001 are significantly different from vehicle-treated animals (only Whitney test; n = 6-8).

도 6은 시간(일)의 함수로서 폰 프레이 헤어 필라멘트를 사용하여 발 도피를 유발시키는데 필요한 힘(g)을 도시하는 막대 그래프이다. PD 198306(3㎎/100㎕)의 단일 발바닥내(intraplantar, i.pl.) 투여 또는 PD 198306(30㎍/10㎕)의 수막강내 주사된 동물의 도피 역치를 처리 1시간 후에 재검사하였다. 결과는 평균 ±1st및 3rd사분값으로 표기한다.**P＜0.01은 비히클-처리된 동물과 유의적으로 상이하다(만-휘트니 t 시험; n = 6 내지 9).Figure 6 is a bar graph showing the force (g) required to induce foot escape using a Von Frey hair filament as a function of time (days). The intraplantar (i.pl.) administration of PD 198306 (3 mg / 100 μl) or the withdrawal threshold of injected animals in the submerged membrane of PD 198306 (30 μg / 10 μl) was rescanned 1 hour after treatment. Results are expressed as mean ± 1 st and 3 rd quartiles. ** P &lt; 0.01 is significantly different from vehicle-treated animals (Bay-Whitney test, n = 6-9).

도 7은 시간(일)의 함수로서 폰 프레이 헤어 필라멘트를 사용하여 발 도피를 유발시키는데 필요한 힘(g)을 도시하는 막대 그래프이다. PD 198306(3㎎/100㎕)의 단일 발바닥내 투여 또는 PD 198306(30㎍/10㎕)의 수막강내 주사된 동물의 도피 역치를 처리 1시간 후에 재검사하였다. 결과는 평균 ±1st및 3rd사분값으로 표기한다.**P＜0.01은 비히클-처리된 동물과 유의적으로 상이하다(만-휘트니 t 시험; n = 6).Figure 7 is a bar graph showing the force (g) required to induce foot escape using the Von Frey hair filament as a function of time (days). The single in-vivo administration of PD 198306 (3 mg / 100 μl) or the reflux threshold of the injected animals in PD 198306 (30 μg / 10 μl) was resentified 1 hour after treatment. Results are expressed as mean ± 1 st and 3 rd quartiles. ** P &lt; 0.01 is significantly different from vehicle-treated animals (Bay-Whitney test, n = 6).

도 8은 폰 프레이 헤어 필라멘트를 사용하여 발 도피를 유발시키는데 필요한 힘(g)을 도시하는 막대 그래프이다. 기준선(BL)은 처리 전에 측정하였다. PD 219622, PD297447, PD184352 또는 PD254552(30㎍/10㎕) 또는 프레가발린(100㎍/10㎕)의 단일 수막강내 투여된 동물의 도피 역치를 처리 30분, 1시간 및 2시간 후에 재검사하였다. 결과는 평균 ±1st및 3rd사분값으로 표기한다.*P＜0.05,**P＜0.01,***P＜0.001은 비히클-처리된 동물과 유의적으로 상이하다(만-휘트니 t 시험; n = 7 내지 8).Figure 8 is a bar graph showing the force (g) required to induce foot escape using a Von Frey hair filament. The baseline (BL) was measured before treatment. The withdrawal thresholds of animals treated with single-membrane intramuscular injection of PD 219622, PD 297422, PD 184352 or PD 254552 (30 μg / 10 μl) or pregabalin (100 μg / 10 μl) were rescanned 30 minutes, 1 hour and 2 hours after treatment . Results are expressed as mean ± 1 st and 3 rd quartiles. * P <0.05, ** P <0.01, *** P <0.001 are significantly different from vehicle-treated animals (only Whitney test; n = 7 to 8).

본원에 개시된 화합물은 약학적으로 활성이다. 예를 들면, 이들은 MEK를 억제한다. MEK 효소는 면역제어(immunomodulation), 염증 및 증식성 질환(예: 암 및 재발협착증(restenosis))과 같은 질환과 관련되는 이중 특이성 키나아제이다.The compounds disclosed herein are pharmaceutically active. For example, they inhibit MEK. MEK enzymes are bispecific kinases involved in diseases such as immunomodulation, inflammation and proliferative diseases such as cancer and restenosis.

증식성 질환은 세포간 신호 시스템 또는 특정 단백질의 신호 변환 메커니즘에서의 결함에 의해 초래된다. 결함으로는 신호 캐스케이드에서 하나 이상의 신호 단백질의 고유 활성 또는 세포 농도면에서의 변화가 포함된다. 세포는 성장 인자를 생산하여 그 자체 수용기에 결합시키며, 이는 자가분비 루프(autocrine loop)를 생성시킨 후 연속적으로 증식을 자극할 수 있다. 세포간 신호 단백질의 돌연변이 또는 과발현은 세포내의 가성 유사분열성 신호(spurious mitogenic signal)를 발생시킬 수 있다. 가장 통상적인 돌연변이중 몇몇은, GTP에 결합되는 경우 활성화되고 GDP에 결합되는 경우 비활성화되는, Ras로서 공지된 단백질(G-단백질)을 암호화하는 유전자에서 발생한다. 상기 언급된 성장 인자 수용기 및 다수의 다른 유사분열성 수용기는 활성화되는 경우 Ras를 GDP-결합된 상태로부터 GTP-결합된 상태로 변환시킨다. 이 신호는 대부분의 세포 유형에서 증식을 위한 절대 필요조건이다. 이 신호 시스템, 특히 Ras-GTP 복합물의 비활성화에서의 결함은 암에서는 통상적인 것으로, 신호 캐스케이드를 아래로 이끌어 내리고, Ras는 임상적으로 활성화시킨다.Proliferative diseases are caused by defects in signal transduction mechanisms of the intercellular signal system or specific proteins. Defects include intrinsic activity of one or more signal proteins in the signal cascade or changes in cell concentration. Cells produce growth factors that bind to their receptors, which can stimulate subsequent proliferation after producing an autocrine loop. Mutations or overexpression of intercellular signaling proteins can generate spurious mitogenic signals in the cells. Some of the most common mutations occur in genes encoding a protein known as Ras (G-protein), which is activated when bound to GTP and inactivated when bound to GDP. The growth factor receptor and many other mitotic receptors mentioned above, when activated, convert Ras from the GDP-linked state to the GTP-linked state. This signal is an absolute requirement for proliferation in most cell types. Defects in the inactivation of this signal system, particularly the Ras-GTP complex, are common in cancer, leading to a signal cascade down, and Ras clinically activating.

활성화된 Ras는 또다시 세린/트레오닌 키나아제의 캐스케이드를 활성화시킨다. 활성 Ras-GTP의 자체 활성화에 필요한 것으로 알려진 키나아제 군중 하나는 Raf 부류이다. 이들은 또다시 MEK(예: MEK1및 MEK2)를 활성화시킨 후, MAP 키나아제, ERK(ERK1및 ERK2)를 활성화시킨다. 유사분열물질에 의한 MAP 키나아제의 활성화는 증식에 있어 필수적인 것으로 보이고; 이 키나아제의 구조적 활성화는 세포 변형을 유발시키는데 충분하다. 다운스트림 Ras 신호화를 예컨대 우성의 음성 Raf-1 단백질을 사용하여 차단하면, 세포 표면 수용기로부터 또는 종양발생성 Ras 돌연변이체로부터 유발되든지 관계없이 유사분열을 완전히 억제할 수 있다. Ras가 그 자체는 단백질 키나아제가 아닐지라도, 이는 예컨대 대부분의 경우 인산화 메커니즘을 통해 Raf 및 다른 키나아제의 활성화에 참여한다. 한번 활성화되면, Raf 및 다른 키나아제는 MEK-1의 경우 2개의 밀접하게 인접한 세린 잔기(S218및 S222)상에서 MEK를 인산화시키며, 이는 키나아제로서 MEK의 활성화를 위한 필수조건이다.MEK는 또다시 단일 아미노산에 의해 분리된 티로신(Y185)과 트레오닌 잔기(T183) 모두에서 MAP 키나아제를 인산화시킨다.Activated Ras again activates the cascade of serine / threonine kinases. One group of kinases known to be required for the self-activation of active Ras-GTP is the Raf class. They again activate MEK (e.g., MEK 1 and MEK 2 ) and then activate MAP kinase, ERK (ERK 1 and ERK 2 ). Activation of MAP kinase by mitotic materials appears to be essential for proliferation; Structural activation of this kinase is sufficient to induce cell transformation. Blocking downstream Ras signaling using, for example, dominant negative Raf-1 protein can completely inhibit mitosis, whether induced from cell surface receptors or from a tumorigenic Ras mutant. Although Ras is not itself a protein kinase, it participates in the activation of Raf and other kinases, for example in most cases via a phosphorylation mechanism. Once activated, Raf and other kinases phosphorylate MEK on two closely adjacent serine residues (S 218 and S 222 ) in the case of MEK-1, which is a prerequisite for the activation of MEK as a kinase. Both tyrosine (Y 185 ) and threonine residues (T 183 ) isolated by a single amino acid phosphorylate MAP kinase.

이 이중 인산화는 MAP 키나아제를 100배 이상 활성화시킨다. 이어, 활성화된 MAP 키나아제는 몇몇 전사 인자와 다른 키나아제를 포함한 다수의 단백질의 인산화를 촉진시킬 수 있다. 이들 다수의 MAP 키나아제 인산화는 타겟 단백질(예: 키나아제, 전사 인자 또는 다른 세포성 단백질)을 유사분열적으로 활성화시킨다. Raf-1 및 MEKK와 더불어, 다른 키나아제는 MEK를 활성화시키고, MEK는 자체적으로 신호 집적화 키나아제인 것으로 나타난다. 현재, MEK는 MAP 키나아제의 인산화에 대해 매우 특이적인 것으로 이해되고 있다. 사실상, MAP 키나아제(ERK) 이외의 MEK를 위한 어떠한 기질에서도, MEK가 MAP 키나아제 인산화 서열을 기초로 하는 펩타이드 또는 심지어 변성된(denatured) MAP 키나아제를 인산화시키지 못한다고 현재까지 입증되어 왔다. MEK는 또한 MAP 키나아제를 인산화시키기 전에는 MAP 키나아제와 강하게 회합하려 하는 것으로 나타나며, 이는 MEK에 의한 MAP 키나아제의 인산화가 2개의 단백질 사이의 강한 상호작용을 사전에 요구할 수 있음을 암시한다. 이 요구조건 및 MEK의 비정상적인 특이성 모두는, MEK의 선택적 억제제(이는 ATP 결합 부위의 통상적인 차단을 통하기보다는 알로스테릭(allosteric) 메커니즘을 통해 작동할 수 있슴)가 발견될 수 있는, 다른 단백질 키나아제에 대한 작용 메커니즘에서의 충분한 차이점을 가질 수 있음을 암시한다.This dual phosphorylation activates MAP kinase more than 100-fold. Activated MAP kinase can then promote phosphorylation of a number of proteins, including some transcription factors and other kinases. These multiple MAP kinase phosphorylation mitigates the activation of target proteins (eg, kinases, transcription factors or other cellular proteins). In addition to Raf-1 and MEKK, other kinases activate MEK and MEK itself appears to be a signal-integrated kinase. Currently, it is understood that MEK is highly specific for the phosphorylation of MAP kinase. Indeed, it has been demonstrated to date that MEK does not phosphorylate MAP kinase phosphorylated sequence-based peptides, or even denatured MAP kinases, for any substrate for MEK other than MAP kinase (ERK). MEK also appears to strongly associate with MAP kinase prior to phosphorylating MAP kinase, suggesting that phosphorylation of MAP kinase by MEK may require a strong interaction between the two proteins in advance. Both this requirement and the abnormal specificity of MEK suggest that other protein kinases, such as the selective inhibitor of MEK, which may be able to work through the allosteric mechanism rather than through the normal interception of the ATP binding site, Lt; Desc / Clms Page number 2 &gt; mechanism of action.

MEK 억제제(PD 198306)의 효과는 신경병증성 동통을 앓는 2마리의 동물 모델에서 폰 프레이 헤어를 사용하는 정적 무해자극통증을 검정함으로써 조사하여 왔다.The effect of the MEK inhibitor (PD 198306) has been investigated by assaying static harmless stimulation pain using von Frey hair in two animal models with neuropathic pain.

PD 198306의 경구 투여(3 내지 30㎎/㎏)는 좌골 신경의 만성 수축 손상(chronic constriction injury, CCI)을 앓는 모델에서 전혀 효과를 나타내지 않았다. 그러나, 반복적인 투여(2일에 걸친 3회 투여) 후, 당뇨병성 신경병증 모델(스트렙토조신(streptosocin))에서 일시적인 효과를 나타냈다. 이는 이들 동물에서 당뇨병 상태에 의해 유발되어 상기 화합물의 중추 작용을 허용하는 혈뇌장벽(blood-brain barrier)의 질환 때문일 수 있다. PD 198306의 수막강내 투여(1 내지 30㎍)는 스트렙토조신 및 신경병증성 동통을 앓는 CCI 모델 모두에서 정적 무해자극통증을 투여량-의존적으로 차단하였는데, 최소 효과 투여량(minimum effective dose, MED)은 각각 3㎍ 및 10㎍이었다. 사용된 최대 투여량(30㎍)은 1시간 이하 동안 정적 무해자극통증을 전반적으로 차단하였다. 수막강내에서 효과적인 것으로 나타난 투여량(30㎍/10㎕)보다 100배 높은 투여량에서의 PD 198306의 발바닥내 투여(3㎎/100㎕)는, 신경병증성 동통 모델중 어디에서도 정적 무해자극통증에 대해 전혀 효과를 나타내지 않았다. 이 발견으로 인해, 전신계 투여 후에 관찰되는 효과의 부족이 확인되며, 상기 화합물의 활성의 중심 부위가 제안된다.Oral administration of PD 198306 (3 to 30 mg / kg) showed no effect in models with chronic constriction injury (CCI) of the sciatic nerve. However, after repeated dosing (3 doses over 2 days), it showed a transient effect in the diabetic neuropathy model (streptosocin). This may be due to a disease of the blood-brain barrier that is caused by the diabetic state in these animals, which allows the central action of the compound. In the intrathecal administration (1 to 30 [mu] g) of PD 198306 dose-dependently blocked static harmless stimulation pain in both the streptozocin and CCI models with neuropathic pain, the minimum effective dose (MED ) Were 3 및 and 10 각각 respectively. The maximum dose (30 μg) used generally blocked static harmless irritation pain for less than 1 hour. The in-plant administration of PD 198306 (3 mg / 100 μl) at a dose 100 times higher than the dose (30 μg / 10 μl) indicated to be effective in the meningioma, No effect on pain. This discovery confirms the lack of effect observed after systemic administration and suggests that the active central site of the compound.

이 연구로부터 본 출원인은 만성 동통을 위한 잠재적인 신규한 치료 도구로서의 MEK 억제제의 용도를 제안할 수 있다. 미래의 뇌투과성 MEK 억제제의 잠재적 부작용, 특히 기억과 관련된 부작용에 대한 연구로 인해, 동통의 치료에서 이 신규한 부류의 화합물에 관한 치료 방향이 제시될 것이다.From this study, Applicants can propose the use of MEK inhibitors as potential new therapeutic tools for chronic pain. Potential side effects of future brain-permeable MEK inhibitors, particularly those related to memory, will be addressed in the treatment of this new class of compounds in the treatment of pain.

A. 용어A. Terms

특정 용어는 하기 정의되며 본원 전체에 걸쳐 그들의 사용례에 의해 정의된다.Certain terms are defined below and are defined throughout the disclosure by their use.

알킬기는 자유 원자가를 갖는 지방족 화합물(즉, 수소 및 탄소원자를 함유하는 하이드로카빌 또는 탄화수소 라디칼 구조)을 포함한다. 알킬기는 직쇄 및 분지쇄 구조를 포함하는 것으로 이해된다. 그 예로는 메틸, 에틸, 프로필, 이소프로필, 부틸, n-부틸, 이소부틸, t-부틸, 펜틸, 이소펜틸, 2,3-디메틸프로필, 헥실, 2,3-디메틸헥실, 1,1-디메틸펜틸, 헵틸 및 옥틸이 포함된다. 사이클로알킬기로는 사이클로프로필, 사이클로부틸, 사이클로펜틸, 사이클로헥실, 사이클로헵틸 및 사이클로옥틸이 포함된다.Alkyl groups include aliphatic compounds having free valencies (i.e., hydrocarbyl or hydrocarbon radical structures containing hydrogen and a carbon atom). The alkyl group is understood to include linear and branched structures. Examples thereof include methyl, ethyl, propyl, isopropyl, butyl, n-butyl, isobutyl, t-butyl, pentyl, isopentyl, 2,3-dimethylpropyl, hexyl, Dimethylpentyl, heptyl and octyl. Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

알킬기는 할로(플루오로, 클로로, 브로모 또는 요오도), 하이드록시, 아미노, 알콕시, 알킬아미노, 디알킬아미노, 사이클로알킬, 아릴, 아릴옥시, 아릴알킬옥시, 헤테로사이클릭 라디칼 및 (헤테로사이클릭 라디칼)옥시로부터 독립적으로 선택된 1, 2 또는 3개 이상의 치환기로 치환될 수 있다. 구체적 예로는 플루오로메틸, 하이드록시에틸, 2,3-디하이드록시에틸, (2- 또는 3-푸라닐)메틸, 사이클로프로필메틸, 벤질옥시에틸, (3-피리디닐)메틸, (2- 또는 3-푸라닐)메틸, (2-티에닐)에틸, 하이드록시프로필, 아미노사이클로헥실, 2-디메틸아미노부틸, 메톡시메틸, N-피리디닐에틸, 디에틸아미노에틸 및 사이클로부틸메틸이 포함된다.The alkyl group may be optionally substituted with one or more groups selected from halo (fluoro, chloro, bromo or iodo), hydroxy, amino, alkoxy, alkylamino, dialkylamino, cycloalkyl, aryl, aryloxy, arylalkyloxy, 2, or 3 substituents independently selected from halogen, cyano, nitro, cyano, nitro, cyano, nitro, cyano, Specific examples include fluoromethyl, hydroxyethyl, 2,3-dihydroxyethyl, (2- or 3-furanyl) methyl, cyclopropylmethyl, benzyloxyethyl, (3- pyridinyl) (2-thienyl) ethyl, hydroxypropyl, aminocyclohexyl, 2-dimethylaminobutyl, methoxymethyl, N-pyridinylethyl, diethylaminoethyl and cyclobutylmethyl do.

알케닐기는 알킬기와 유사하지만, 하나 이상의 이중결합(2개의 인접한 sp2탄소원자)을 갖는다. 이중결합 및 존재한다면 치환기의 배치(placement)에 따라, 이중결합의 기하형태는 entgegen(E) 또는 zusammen(Z), 시스(cis) 또는 트랜스(trans)일 수 있다. 유사하게, 알키닐기는 하나 이상의 삼중결합(2개의 인접한 sp 탄소원자)을 갖는다. 불포화 알케닐 또는 알키닐기는 각각 하나 이상의 이중결합 또는 삼중결합, 또는 이들의 혼합물을 가질 수 있고, 알킬기와 마찬가지로, 불포화 기는 직쇄 또는 분지쇄일 수 있고, 이들은 알킬기에 관해 상기에서 기술하고 실시예에 의한 개시내용 전체에 걸쳐 기술된 바와 같이 치환될 수 있다. 알케닐, 알키닐 및 치환된 형태의 예로는 시스-2-부테닐, 트랜스-2-부테닐, 3-부티닐, 3-페닐-2-프로피닐, 3-(2'-플루오로페닐)-2-프로피닐, 3-메틸(5-페닐)-4-펜티닐, 2-하이드록시-2-프로피닐, 2-메틸-2-프로피닐, 2-프로페닐, 4-하이드록시-3-부티닐, 3-(3-플루오로페닐)-2-프로피닐 및 2-메틸-2-프로페닐이 포함된다. 화학식 I에서, 알케닐 및 알키닐은 예컨대 C2-4또는 C2-8일 수 있으며, C3-4또는 C3-8인 것이 바람직하다.The alkenyl group is similar to an alkyl group, but has at least one double bond (two adjacent sp 2 carbon atoms). Depending on the placement of the double bond and the substituent, if present, the geometry of the double bond may be entgegen (E) or zusammen (Z), cis or trans. Similarly, an alkynyl group has at least one triple bond (two adjacent sp carbon atoms). The unsaturated alkenyl or alkynyl group may each have at least one double bond or a triple bond, or a mixture thereof, and like the alkyl group, the unsaturated group may be straight-chain or branched, and these may be the same or different, May be substituted as described throughout the disclosure. Examples of the alkenyl, alkynyl and substituted forms include cis-2-butenyl, trans-2-butenyl, 3-butynyl, 3-phenyl-2- propynyl, 3- (2'- Propyl, 2-propenyl, 2-propenyl, 4-hydroxy-3-propenyl, -Butynyl, 3- (3-fluorophenyl) -2-propynyl and 2-methyl-2-propenyl. In formula (I), alkenyl and alkynyl may be, for example, C 2-4 or C 2-8 , preferably C 3-4 or C 3-8 .

치환된 탄화수소 라디칼의 더욱 일반적인 형태로는 하이드록시알킬, 하이드록시알케닐, 하이드록시알키닐, 하이드록시사이클로알킬, 하이드록시아릴, 및 이들에 상응하는, 접두사 아미노-, 할로-(예: 플루오로-, 클로로- 또는 브로모-), 니트로-, 알킬-, 페닐-, 사이클로알킬- 등의 형태, 또는 치환기들의 조합이 포함된다. 따라서, 화학식 I에 따르면, 치환된 알킬로는 하이드록시알킬, 아미노알킬, 니트로알킬, 할로알킬, 알킬알킬(분지된 알킬, 예컨대 메틸펜틸), (사이클로알킬)알킬,페닐알킬, 알콕시, 알킬아미노알킬, 디알킬아미노알킬, 아릴알킬, 아릴옥시알킬, 아릴알킬옥시알킬, (헤테로사이클릭 라디칼)알킬, 및 (헤테로사이클릭 라디칼)옥시알킬이 포함된다. 따라서, R1로는 하이드록시알킬, 하이드록시알케닐, 하이드록시알키닐, 하이드록시사이클로알킬, 하이드록시아릴, 아미노알킬, 아미노알케닐, 아미노알키닐, 아미노사이클로알킬, 아미노아릴, 알킬알케닐, (알킬아릴)알킬, (할로아릴)알킬, (하이드록시아릴)알키닐 등이 포함된다. 유사하게, RA로는 하이드록시알킬 및 아미노아릴이 포함되고, RB로는 하이드록시알킬, 아미노알킬 및 하이드록시알킬(헤테로사이클릭 라디칼)알킬이 포함된다.More typical forms of substituted hydrocarbon radicals include, but are not limited to, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, hydroxycycloalkyl, hydroxyaryl, and the corresponding prefixed amino-, halo- -, chloro- or bromo-), nitro-, alkyl-, phenyl-, cycloalkyl-, etc., or combinations of substituents. Thus, according to Formula I, substituted alkyl is optionally substituted with one or more substituents selected from the group consisting of hydroxyalkyl, aminoalkyl, nitroalkyl, haloalkyl, alkylalkyl (branched alkyl such as methylpentyl), (cycloalkyl) alkyl, phenylalkyl, alkoxy, alkylamino Alkyl, dialkylaminoalkyl, arylalkyl, aryloxyalkyl, arylalkyloxyalkyl, (heterocyclic radical) alkyl, and (heterocyclic radical) oxyalkyl. Thus, R 1 is preferably selected from the group consisting of hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, hydroxycycloalkyl, hydroxyaryl, aminoalkyl, aminoalkenyl, aminoalkynyl, aminocycloalkyl, aminoaryl, alkylalkenyl, (Alkylaryl) alkyl, (haloaryl) alkyl, (hydroxyaryl) alkynyl, and the like. Similarly, R A includes hydroxyalkyl and aminoaryl, and R B includes hydroxyalkyl, aminoalkyl, and hydroxyalkyl (heterocyclic radical) alkyl.

헤테로아릴을 포함하되 이에 한정되지 않는 헤테로사이클릭 라디칼로는, 푸릴, 옥사졸릴, 이속사졸릴, 티오페닐, 티아졸릴, 피롤릴, 이미다졸릴, 1,3,4-트리아졸릴, 테트라졸릴, 피리디닐, 피리미디닐, 피리다지닐, 인돌릴, 및 그들의 비방향족 대응물(counterpart)이 포함된다. 헤테로사이클릭 라디칼의 추가 예로는 피페리딜, 퀴놀릴, 이소티아졸릴, 피페리디닐, 모폴리닐, 피페라지닐, 테트라하이드로푸릴, 테트라하이드로피롤릴, 피롤리디닐, 옥타하이드로인돌릴, 옥타하이드로벤조티오푸라닐 및 옥타하이드로벤조푸라닐이 포함된다.Heterocyclic radicals including but not limited to heteroaryl include furyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl, pyrrolyl, imidazolyl, 1,3,4-triazolyl, tetrazolyl, Pyridinyl, pyrimidinyl, pyridazinyl, indolyl, and their nonaromatic counterparts. Further examples of heterocyclic radicals include piperidyl, quinolyl, isothiazolyl, piperidinyl, morpholinyl, piperazinyl, tetrahydrofuryl, tetrahydropyrrolyl, pyrrolidinyl, octahydroindolyl, octa Tetrahydrofuranyl, hydrobenzothiopyranyl and octahydrobenzofuranyl.

선택적 MEK1 또는 MEK2 억제제는 다른 효소(예: MKK2, PKC, Cdk2A, 포스포릴라아제 키나아제, EGF 및 PDGF 수용기 키나아제) 및 C-src를 실질적으로 억제시키지 않고서 MEK1 또는 MEK2 효소를 각각 억제하는 화합물이다. 일반적으로, 선택적 MEK1 또는 MEK2 억제제는 상기 명명된 다른 효소중 하나에 대한 IC50의 1/50 이상인MEK1 또는 MEK2에 대한 IC50을 갖는다. 바람직하게는, 선택적 억제제는 상기 명명된 효소중 하나 또는 하나 이상의 IC50보다 1/100 이상, 더욱 바람직하게는 1/500 이상, 더욱더 바람직하게는 1/1000, 1/5000 또는 그 미만 이상의 IC50을 갖는다.The selective MEK1 or MEK2 inhibitor is a compound that inhibits the MEK1 or MEK2 enzyme, respectively, without substantially inhibiting other enzymes (e.g., MKK2, PKC, Cdk2A, phosphorylase kinase, EGF and PDGF receptor kinase) and C-src. In general, selective MEK1 or MEK2 inhibitor has an IC 50 for the MEK1 or MEK2 less than 1/50 of the IC 50 for one of the named other enzymes. Preferably, a selective inhibitor has the named one enzyme or more than 1/100 or more than one IC 50, more preferably 1/500, and even more preferably 1/1000, 1/5000 or less than 50 or more IC Respectively.

B. 화합물B. Compound

본 발명의 한 양태는 발명의 요약 부분에서 화학식 I에 도시되어 개시된 화합물에 관한 것이다.One aspect of the present invention relates to compounds disclosed in formula I in the Summary of the Invention.

본 발명의 양태는 (a) R1이 브로모 또는 클로로인 화합물, (b) R2가 플루오로인 화합물, (c) R3이 H인 화합물, (d) R2및 R3이 각각 H인 화합물, (e) R2및 R3이 각각 플루오로인 화합물, (f) R1이 브로모인 화합물, (g) R1, R2및 R3이 각각 플루오로인 화합물, (h) R2가 니트로인 화합물, (i) R3이 H인 화합물, (j) R4가 클로로인 화합물, (k) R4가 메틸인 화합물, (l) R5가 H인 화합물, (m) R5가 CH3인 화합물, (n) X1이 O 또는 S인 화합물, (o) X1이 NH 또는 NCH3인 화합물, (p) X2가 OH, SH 또는 NH2인 화합물, (q) X2가 OH인 화합물, (r) X2가 NHRE인 화합물, (s) R4가 H인 화합물, (t) R4가 클로로 또는 메틸인 화합물, 또는 이들의 조합을 포함한다.Aspect of the present invention is (a) R 1 is bromo or chloro compound, (b) R 2 is a fluoro compound, (c) R 3 is the compound H, (d) R 2 and R 3 are each H the compound, (e) R 2 and R 3 of the compound is a fluoroalkyl, respectively, (f) R 1 is bromo gathered compounds, (g) R 1, R 2 and R 3 of the compound is a fluoroalkyl, respectively, (h) R 2 is nitro the compound, (i) R 3 is H the compound, (j) R 4 is chloro compound, (k) R 4 is methyl a compound, (l) R 5 is H compound, (m) R 5 is CH 3 the compound, (n) is X 1 is O or S compound, (o) of X 1 is NH or NCH 3 compound, (p) the compound X 2 is OH, SH or NH 2, (q) X 2 is an OH compound, (r) include those wherein X 2 is NHR E compound (s) of the compound R 4 is H, (t) R 4 is chloro or methyl, or a combination thereof.

바람직하게는, 헤테로사이클릭 라디칼상의 치환기중 하나가 알케닐 또는 알키닐기인 경우, 이중결합 또는 삼중결합은 각각 헤테로원자인 경우의 결합 지점에 인접하게 위치하지 않는다. 예를 들면, 이러한 상황에서, 치환기는 프로프-2-이닐또는 부트-2 또는 3-에닐인 것이 바람직하며, 프로프-1-이닐 또는 부트-1-에닐은 이보다 덜 바람직하다.Preferably, when one of the substituents on the heterocyclic radical is an alkenyl or alkynyl group, the double bond or triple bond is not located adjacent to the point of attachment where each is a heteroatom. For example, in this situation the substituent is preferably prop-2-ynyl or bo-2 or 3-enyl, and prop-1-ynyl or but-1-enyl is less preferred.

화합물의 예로는 하기의 화합물이 포함된다:Examples of compounds include the following compounds:

[5-플루오로-2-(1H-테트라졸-5-일)-페닐]-(4-요오도-2-메틸-페닐)-아민;[5-fluoro-2- (lH-tetrazol-5-yl) -phenyl] - (4-iodo-2-methyl-phenyl) -amine;

[2,3-디플루오로-6-(1H-테트라졸-5-일)-페닐]-(4-요오도-2-메틸-페닐)-아민;[2,3-difluoro-6- (lH-tetrazol-5-yl) -phenyl] - (4-iodo-2-methyl-phenyl) -amine;

(4-요오도-2-메틸-페닐)-[2,3,4-트리플루오로-6-(1H-테트라졸-5-일)-페닐]-아민;(4-iodo-2-methyl-phenyl) - [2,3,4-trifluoro-6- (lH-tetrazol-5-yl) -phenyl] -amine;

[4-브로모-2,3-디플루오로-6-(1H-테트라졸-5-일)-페닐]-(4-요오도-2-메틸-페닐)-아민;[4-Bromo-2,3-difluoro-6- (lH-tetrazol-5-yl) -phenyl] - (4-iodo-2-methyl-phenyl) -amine;

[5-플루오로-4-니트로-2-(1H-테트라졸-5-일)-페닐]-(4-요오도-2-메틸-페닐)-아민;[5-Fluoro-4-nitro-2- (lH-tetrazol-5-yl) -phenyl] - (4-iodo-2-methyl-phenyl) -amine;

[2-(4,4-디메틸-4,5-디하이드로-옥사졸-2-일)-5-플루오로-페닐]-(4-요오도-2-메틸-페닐)-아민;[2- (4,4-Dimethyl-4,5-dihydro-oxazol-2-yl) -5-fluoro-phenyl] - (4-iodo-2-methyl-phenyl) -amine;

[6-(4,4-디메틸-4,5-디하이드로-옥사졸-2-일)-2,3-디플루오로-페닐]-(4-요오도-2-메틸-페닐)-아민;Phenyl] - (4-iodo-2-methyl-phenyl) -amine &lt; EMI ID = ;

[6-(4,4-디메틸-4,5-디하이드로-옥사졸-2-일)-2,3,4-트리플루오로-페닐]-(4-요오도-2-메틸-페닐)-아민;Phenyl) - (4-iodo-2-methyl-phenyl) - &lt; / RTI & - amine;

[4-브로모-6-(4,4-디메틸-4,5-디하이드로-옥사졸-2-일)-2,3-디플루오로-페닐]-(4-요오도-2-메틸-페닐)-아민;(4-bromo-6- (4,4-dimethyl-4,5-dihydro-oxazol-2-yl) -2,3- -Phenyl) -amine &lt; / RTI &gt;

[2-(4,4-디메틸-4,5-디하이드로-옥사졸-2-일)-5-플루오로-4-니트로-페닐]-(4-요오도-2-메틸-페닐)-아민;4-Nitro-phenyl] - (4-iodo-2-methyl-phenyl) - Amine;

5-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-[1,3,4]티아디아졸-2-올;5- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] - [1,3,4] thiadiazol-2-ol;

5-[3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-[1,3,4]티아디아졸-2-올;5- [3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] - [1,3,4] thiadiazol-2-ol;

5-[3,4,5-트리플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-[1,3,4]티아디아졸-2-올;5- [3,4,5-Trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] - [1,3,4] thiadiazol-2-ol;

5-[5-브로모-3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-[1,3,4]티아디아졸-2-올;5- [5-Bromo-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] - [1,3,4] thiadiazol-2-ol;

5-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-5-니트로-페닐]-[1,3,4]티아디아졸-2-올;5- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl] - [1,3,4] thiadiazol-2-ol;

5-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-[1,3,4]옥사디아졸-2-올;5- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] - [1,3,4] oxadiazol-2-ol;

5-[3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-[1,3,4]옥사디아졸-2-올;5- [3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] - [1,3,4] oxadiazol-2-ol;

5-[3,4,5-트리플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-[1,3,4]옥사디아졸-2-올;5- [3,4,5-Trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] - [1,3,4] oxadiazol-2-ol;

5-[5-브로모-3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-[1,3,4]옥사디아졸-2-올;5- [5-Bromo-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] - [1,3,4] oxadiazol-2-ol;

5-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-5-니트로-페닐]-[1,3,4]옥사디아졸-2-올;5- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl] - [1,3,4] oxadiazol-2-ol;

5-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-4H-[1,2,4]트리아졸-3-올;5- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -4H- [1,2,4] triazol-3-ol;

5-[3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-4H-[1,2,4]트리아졸-3-올;5- [3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -4H- [1,2,4] triazol-3-ol;

5-[3,4,5-트리플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-4H-[1,2,4]트리아졸-3-올;5- [3,4,5-Trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -4H- [1,2,4] triazol-3-ol;

5-[5-브로모-3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-4H-[1,2,4]트리아졸-3-올; 및2-methyl-phenylamino) -phenyl] -4H- [1,2,4] triazol-3-ol ; And

5-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-5-니트로-페닐]-4H-[1,2,4]트리아졸-3-올.5- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl] -4H- [1,2,4] triazol-3-ol.

추가 예로는 하기 화합물이 포함된다:Further examples include the following compounds:

5-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-[1,3,4]티아디아졸-2-일아민;5- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] - [1,3,4] thiadiazol-2-ylamine;

5-[3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-[1,3,4]티아디아졸-2-일아민;5- [3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] - [1,3,4] thiadiazol-2-ylamine;

5-[3,4,5-트리플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-[1,3,4]티아디아졸-2-일아민;5- [3,4,5-Trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] - [1,3,4] thiadiazol-2-ylamine;

5-[5-브로모-3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-[1,3,4]티아디아졸-2-일아민;Methyl-phenylamino) -phenyl] - [1,3,4] thiadiazol-2-ylamine &lt; / RTI &gt;;

5-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-5-니트로-페닐]-[1,3,4]티아디아졸-2-일아민;5- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl] - [1,3,4] thiadiazol-2-ylamine;

5-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-[1,3,4]옥사디아졸-2-일아민;5- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] - [1,3,4] oxadiazol-2-ylamine;

5-[3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-[1,3,4]옥사디아졸-2-일아민;5- [3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] - [1,3,4] oxadiazol-2-ylamine;

5-[3,4,5-트리플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-[1,3,4]옥사디아졸-2-일아민;5- [3,4,5-Trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] - [1,3,4] oxadiazol-2-ylamine;

5-[5-브로모-3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-[1,3,4]옥사디아졸-2-일아민;Phenyl] - [1,3,4] oxadiazol-2-ylamine &lt; / RTI &gt;;

5-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-5-니트로-페닐]-[1,3,4]옥사디아졸-2-일아민;5- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl] - [1,3,4] oxadiazol-2-ylamine;

5-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-4H-[1,2,4]트리아졸-3-일아민;5- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -4H- [l, 2,4] triazol-3-ylamine;

5-[3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-4H-[1,2,4]트리아졸-3-일아민;5- [3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -4H- [1,2,4] triazol-3-ylamine;

5-[3,4,5-트리플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-4H-[1,2,4]트리아졸-3-일아민;5- [3,4,5-Trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -4H- [l, 2,4] triazol-3-ylamine;

5-[5-브로모-3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-4H-[1,2,4]트리아졸-3-일아민;Phenyl] -4H- [l, 2,4] triazol-3-yl-lH-pyrrolo [ Amine;

5-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-5-니트로-페닐]-4H-[1,2,4]트리아졸-3-일아민;5- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl] -4H- [1,2,4] triazol-3-ylamine;

5-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-[1,3,4]티아디아졸-2-티올;5- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] - [1,3,4] thiadiazole-2-thiol;

5-[3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-[1,3,4]티아디아졸-2-티올;5- [3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] - [1,3,4] thiadiazole-2-thiol;

5-[3,4,5-트리플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-[1,3,4]티아디아졸-2-티올;5- [3,4,5-Trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] - [1,3,4] thiadiazole-2-thiol;

5-[5-브로모-3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-[1,3,4]티아디아졸-2-티올;5- [5-Bromo-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] - [1,3,4] thiadiazole-2-thiol;

5-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-5-니트로-페닐]-[1,3,4]티아디아졸-2-티올;5- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl] - [1,3,4] thiadiazole-2-thiol;

5-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-[1,3,4]옥사디아졸-2-티올;5- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] - [1,3,4] oxadiazole-2-thiol;

5-[3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-[1,3,4]옥사디아졸-2-티올;5- [3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] - [1,3,4] oxadiazole-2-thiol;

5-[3,4,5-트리플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-[1,3,4]옥사디아졸-2-티올;5- [3,4,5-Trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] - [1,3,4] oxadiazole-2-thiol;

5-[5-브로모-3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-[1,3,4]옥사디아졸-2-티올;5- [5-Bromo-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] - [1,3,4] oxadiazole-2-thiol;

5-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-5-니트로-페닐]-[1,3,4]옥사디아졸-2-티올;5- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl] - [1,3,4] oxadiazole-2-thiol;

5-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-4H-[1,2,4]트리아졸-3-티올;5- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -4H- [1,2,4] triazole-3-thiol;

5-[3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-4H-[1,2,4]트리아졸-3-티올;5- [3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -4H- [1,2,4] triazole-3-thiol;

5-[3,4,5-트리플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-4H-[1,2,4]트리아졸-3-티올;5- [3,4,5-Trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -4H- [1,2,4] triazole-3-thiol;

5-[5-브로모-3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-4H-[1,2,4]트리아졸-3-티올; 및Methyl-phenylamino) -phenyl] -4H- [1,2,4] triazole-3-thiol &lt; / RTI &gt;; And

5-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-5-니트로-페닐]-4H-[1,2,4]트리아졸-3-티올.5- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl] -4H- [1,2,4] triazole-3-thiol.

또다른 추가 예로는 하기 화합물이 포함된다:Still further examples include the following compounds:

5-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-이소티아졸-3-올;5- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -isothiazol-3-ol;

5-[3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-이소티아졸-3-올;5- [3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -isothiazol-3-ol;

5-[3,4,5-트리플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-이소티아졸-3-올;5- [3,4,5-Trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -isothiazol-3-ol;

5-[5-브로모-3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-이소티아졸-3-올;5- [5-Bromo-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -isothiazol-3-ol;

5-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-5-니트로-페닐]-이소티아졸-3-올;5- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl] -isothiazol-3-ol;

5-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-이속사졸-3-올;5- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -isoxazol-3-ol;

5-[3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-이속사졸-3-올;5- [3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -isoxazol-3-ol;

5-[3,4,5-트리플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-이속사졸-3-올;5- [3,4,5-Trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -isoxazol-3-ol;

5-[5-브로모-3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-이속사졸-3-올;5- [5-Bromo-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -isoxazol-3-ol;

5-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-5-니트로-페닐]-이속사졸-3-올;5- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl] -isoxazol-3-ol;

5-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-1H-피라졸-3-올;5- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -lH-pyrazol-3-ol;

5-[3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-1H-피라졸-3-올;5- [3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -lH-pyrazol-3-ol;

5-[3,4,5-트리플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-1H-피라졸-3-올;5- [3,4,5-Trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -lH-pyrazol-3-ol;

5-[5-브로모-3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-1H-피라졸-3-올;5- [5-Bromo-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -lH-pyrazol-3-ol;

5-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-5-니트로-페닐]-1H-피라졸-3-올;5- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl] -1H-pyrazol-3-ol;

4-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-이소티아졸-3-올;4- [4-fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -isothiazol-3-ol;

4-[3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-이소티아졸-3-올;4- [3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -isothiazol-3-ol;

4-[3,4,5-트리플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-이소티아졸-3-올;4- [3,4,5-Trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -isothiazol-3-ol;

4-[5-브로모-3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-이소티아졸-3-올;4- [5-Bromo-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -isothiazol-3-ol;

4-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-5-니트로-페닐]-이소티아졸-3-올;4- [4-fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl] -isothiazol-3-ol;

4-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-이속사졸-3-올;4- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -isoxazol-3-ol;

4-[3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-이속사졸-3-올;4- [3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -isoxazol-3-ol;

4-[3,4,5-트리플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-이속사졸-3-올;4- [3,4,5-Trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -isoxazol-3-ol;

4-[5-브로모-3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-이속사졸-3-올;4- [5-Bromo-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -isoxazol-3-ol;

4-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-5-니트로-페닐]-이속사졸-3-올;4- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl] -isoxazol-3-ol;

4-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-1-메틸-1H-피라졸-3-올;4- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -l-methyl-lH-pyrazol-3-ol;

4-[3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-1-메틸-1H-피라졸-3-올;4- [3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -1-methyl-1H-pyrazol-3-ol;

1-메틸-4-[3,4,5-트리플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-1H-피라졸-3-올;L-Methyl-4- [3,4,5-trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -lH-pyrazol-3-ol;

4-[5-브로모-3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-1-메틸-1H-피라졸-3-올; 및4- [5-Bromo-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -1-methyl-1H-pyrazol-3-ol; And

4-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-5-니트로-페닐]-1-메틸-1H-피라졸-3-올.4- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl] -1-methyl-1H-pyrazol-3-ol.

본 발명은 또한 하기 화합물에 관한 것이다:The present invention also relates to the following compounds:

5-[2-(2-아미노-4-요오도-페닐아미노)-4-플루오로-페닐]-1-메틸-1H-[1,2,3]트리아졸-4-올;5- [2- (2-Amino-4-iodo-phenylamino) -4-fluoro-phenyl] -1-methyl-1H- [1,2,3] triazol-4-ol;

5-[2-(2-아미노-4-요오도-페닐아미노)-3,4-디플루오로-페닐]-1-메틸-1H-[1,2,3]트리아졸-4-올;5- [2- (2-Amino-4-iodo-phenylamino) -3,4-difluoro-phenyl] -1-methyl-1H- [1,2,3] triazol-4-ol;

5-[2-(2-아미노-4-요오도-페닐아미노)-3,4,5-트리플루오로-페닐]-1-메틸-1H-[1,2,3]트리아졸-4-올;Phenyl] -1-methyl-1H- [1,2,3] triazol-4- Come;

5-[2-(2-아미노-4-요오도-페닐아미노)-5-브로모-3,4-디플루오로-페닐]-1-메틸-1H-[1,2,3]트리아졸-4-올;5-Bromo-3,4-difluoro-phenyl] -1-methyl-1H- [1,2,3] triazole 4-ol;

5-[2-(2-아미노-4-요오도-페닐아미노)-4-플루오로-5-니트로-페닐]-1-메틸-1H-[1,2,3]트리아졸-4-올;5-Nitro-phenyl] -1-methyl-1H- [1,2,3] triazol-4-ol ;

5-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-3-메틸-3H-[1,2,3]트리아졸-4-올;5- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -3-methyl-3H- [1,2,3] triazol-4-

5-[3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-3-메틸-3H-[1,2,3]트리아졸-4-올;5- [3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -3-methyl-3H- [1,2,3] triazol-4-ol;

3-메틸-5-[3,4,5-트리플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-3H-[1,2,3]트리아졸-4-올;Methyl-5- [3,4,5-trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -3H- [1,2,3] triazol- Come;

5-[5-브로모-3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-3-메틸-3H-[1,2,3]트리아졸-4-올;Phenyl] -3-methyl-3H- [1,2,3] triazole &lt; / RTI &gt;4-ol;

5-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-5-니트로-페닐]-3-메틸-3H-[1,2,3]트리아졸-4-올;Phenyl] -3-methyl-3H- [1,2,3] triazol-4-ol &lt; / RTI &gt;;

4-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-2-메틸-2H-피라졸-3-올;4- [4-fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -2-methyl-2H-pyrazol-3-ol;

4-[3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-2-메틸-2H-피라졸-3-올;4- [3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -2-methyl-2H-pyrazol-3-ol;

2-메틸-4-[3,4,5-트리플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-2H-피라졸-3-올;2-Methyl-4- [3,4,5-trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -2H-pyrazol-3-ol;

4-[5-브로모-3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-2-메틸-2H-피라졸-3-올;4- [5-Bromo-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -2-methyl-2H-pyrazol-3-ol;

4-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-5-니트로-페닐]-2-메틸-2H-피라졸-3-올;4- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl] -2-methyl-2H-pyrazol-3-ol;

1-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-4-메틸-1,4-디하이드로-테트라졸-5-온;1- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -4-methyl-1,4-dihydro-tetrazol-5-one;

1-[3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-4-메틸-1,4-디하이드로-테트라졸-5-온;L- [3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -4-methyl-l, 4-dihydro-tetrazol-5-one;

1-메틸-4-[3,4,5-트리플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-1,4-디하이드로-테트라졸-5-온;L-Methyl-4- [3,4,5-trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -1,4-dihydro-tetrazol-5-one;

1-[5-브로모-3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-4-메틸-1,4-디하이드로-테트라졸-5-온;Methyl-phenylamino) -phenyl] -4-methyl-l, 4-dihydro-tetrazole-5 -On;

1-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-5-니트로-페닐]-4-메틸-1,4-디하이드로-테트라졸-5-온;1- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl] -4-methyl-1,4-dihydro-tetrazol-5-one;

1-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-1H-[1,2,3]트리아졸-4-올;L- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -lH- [l, 2,3] triazol-4-

1-[3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-1H-[1,2,3]트리아졸-4-올;L- [3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -1H- [1,2,3] triazol-4-ol;

1-[3,4,5-트리플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-1H-[1,2,3]트리아졸-4-올;L- [3,4,5-Trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -lH- [l, 2,3] triazol-4-

1-[5-브로모-3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-1H-[1,2,3]트리아졸-4-올; 및Phenyl] -lH- [l, 2,3] triazol-4-ol &lt; / RTI &gt;; And

1-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-5-니트로-페닐]-1H-[1,2,3]트리아졸-4-올.1- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl] -1 H- [1,2,3] triazol-

본 발명의 추가 예로는 하기 화합물이 포함된다:Further examples of the present invention include the following compounds:

3-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-2H-이속사졸-5-온;3- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -2H-isoxazol-5-one;

3-[3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-2H-이속사졸-5-온;3- [3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -2H-isoxazol-5-one;

3-[3,4,5-트리플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-2H-이속사졸-5-온;3- [3,4,5-Trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -2H-isoxazol-5-one;

3-[5-브로모-3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-2H-이속사졸-5-온;3- [5-Bromo-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -2H-isoxazol-5-one;

3-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-5-니트로-페닐]-2H-이속사졸-5-온;3- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl] -2H-isoxazol-5-one;

[5-플루오로-2-(2-옥소-2,3-디하이드로-2I＞4_-[1,2,3,5]옥사티아디아졸-4-일)-페닐]-(4-요오도-2-메틸-페닐)-아민;4-yl) - phenyl] - (4-iodo-4-methylpiperazin-1- Methyl-phenyl) -amine &lt; / RTI &gt;

[2,3-디플루오로-6-(2-옥소-2,3-디하이드로-2I＞4_-[1,2,3,5]옥사티아디아졸-4-일)-페닐]-(4-요오도-2-메틸-페닐)-아민;[2,3-difluoro-6- (2-oxo-2,3-dihydro-2I> 4 _- [1,2,3,5] oxathiadiazol- 4-iodo-2-methyl-phenyl) -amine;

(4-요오도-2-메틸-페닐)-[2,3,4-트리플루오로-6-(2-옥소-2,3-디하이드로-2I＞4_-[1,2,3,5]옥사티아디아졸-4-일)-페닐]-아민;Methyl-phenyl) - [2,3,4-trifluoro-6- (2-oxo-2,3-dihydro- ] Oxathiadiazol-4-yl) -phenyl] -amine;

[4-브로모-2,3-디플루오로-6-(2-옥소-2,3-디하이드로-2I＞4_-[1,2,3,5]옥사티아디아졸-4-일)-페닐]-(4-요오도-2-메틸-페닐)-아민;4-Bromo-2,3-difluoro-6- (2-oxo-2,3-dihydro- -Phenyl] - (4-iodo-2-methyl-phenyl) -amine;

[5-플루오로-4-니트로-2-(2-옥소-2,3-디하이드로-2I＞4_-[1,2,3,5]옥사티아디아졸-4-일)-페닐]-(4-요오도-2-메틸-페닐)-아민;[5-fluoro-4-nitro-2- (2-oxo-2,3-dihydro-2I.4_- [1,2,3,5] oxathiadiazol- (4-iodo-2-methyl-phenyl) -amine;

4-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-4H-이속사졸-5-온;4- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -4H-isoxazol-5-one;

4-[3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-4H-이속사졸-5-온;4- [3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -4H-isoxazol-5-one;

4-[3,4,5-트리플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-4H-이속사졸-5-온;4- [3,4,5-Trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -4H-isoxazol-5-one;

4-[5-브로모-3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-4H-이속사졸-5-온; 및4- [5-Bromo-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -4H-isoxazol-5-one; And

4-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-5-니트로-페닐]-4H-이속사졸-5-온.4- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl] -4H-isoxazol- 5- one.

R1이 또한 SO2NRGRH이거나, R1및 R2가 이들이 결합된 벤젠 고리와 함께 인돌, 이소인돌, 벤조푸란, 벤조티오펜, 인다졸, 벤즈이미다졸 또는 벤즈티오아졸을 구성하는 추가의 화합물로는 하기의 군들이 포함된다:R 1 is also SO 2 NR G R H or R 1 and R 2 together with the benzene ring to which they are attached form an indole, isoindole, benzofuran, benzothiophene, indazole, benzimidazole or benzthioazole Additional compounds include the following groups:

제 1 군Group 1

(1) 2-플루오로-5-(5-하이드록시-1,3,4-옥사디아졸-2-일)-4-(4-요오도-2-메틸-페닐아미노)-벤젠설폰아미드;(1) Synthesis of 2-fluoro-5- (5-hydroxy-1,3,4-oxadiazol-2-yl) -4- (4-iodo-2-methyl- phenylamino) ;

(2) 4-(2-클로로-4-요오도-페닐아미노)-2-플루오로-5-(5-하이드록시-1,3,4-옥사디아졸-2-일)-N-메틸-벤젠설폰아미드;(2-chloro-4-iodo-phenylamino) -2-fluoro-5- (5- - benzenesulfonamide;

(3) 2,3-디플루오로-5-(5-하이드록시-1,3,4-옥사디아졸-2-일)-4-(4-요오도-2-메틸-페닐아미노)-N,N-디메틸-벤젠설폰아미드;(3) 2,3-difluoro-5- (5-hydroxy-1,3,4-oxadiazol-2-yl) -4- N, N-dimethyl-benzenesulfonamide;

(4) 4-(2-클로로-4-요오도-페닐아미노)-2,3-디플루오로-5-(5-하이드록시-1,3,4-옥사디아졸-2-일)-N-메틸-N-(3-모폴린-4-일-프로필)-벤젠설폰아미드;(4) Synthesis of 4- (2-chloro-4-iodo-phenylamino) -2,3- difluoro-5- (5-hydroxy- 1,3,4-oxadiazol- N-methyl-N- (3-morpholin-4-yl-propyl) -benzenesulfonamide;

(5) 2-플루오로-5-(5-하이드록시-1,3,4-옥사디아졸-2-일)-4-(4-요오도-페닐아미 노)-N-[2-(2-메톡시-에톡시)-에틸]-벤젠설폰아미드; 및(5) Synthesis of 2-fluoro-5- (5-hydroxy-1,3,4-oxadiazol-2-yl) -4- (4-iodo-phenylamino) -N- [2- 2-methoxy-ethoxy) -ethyl] -benzenesulfonamide; And

(6) N-(2-디메틸아미노-에틸)-2-플루오로-5-(5-하이드록시-1,3,4-옥사디아졸-2- 일)-4-(4-요오도-페닐아미노)-N-메틸-벤젠설폰아미드.(6) Synthesis of N- (2-dimethylamino-ethyl) -2-fluoro-5- (5-hydroxy-1,3,4-oxadiazol- Phenylamino) -N-methyl-benzenesulfonamide. &Lt; / RTI &gt;

제 2 군Group 2

(1) 5-(5-아미노-1,3,4-옥사디아졸-2-일)-2-플루오로-4-(4-요오도-2-메틸-페닐아미노)-벤젠설폰아미드;(1) 5- (5-amino-1,3,4-oxadiazol-2-yl) -2-fluoro-4- (4-iodo-2-methyl-phenylamino) -benzenesulfonamide;

(2) 5-(5-아미노-1,3,4-옥사디아졸-2-일)-4-(2-클로로-4-요오도-페닐아미노)-2-플루오로-벤젠설폰아미드;(2) 5- (5-Amino-1,3,4-oxadiazol-2-yl) -4- (2-chloro-4-iodo-phenylamino) -2-fluoro-benzenesulfonamide;

(3) 5-(5-아미노-1,3,4-옥사디아졸-2-일)-2,3-디플루오로-4-(4-요오도-2-메틸-페닐아미노)-벤젠설폰아미드;(3) Synthesis of 5- (5-amino-1,3,4-oxadiazol-2-yl) -2,3- difluoro-4- (4- Sulfonamide;

(4) 5-(5-아미노-1,3,4-옥사디아졸-2-일)-4-(2-클로로-4-요오도-페닐아미노)-2,3-디플루오로-벤젠설폰아미드;(4) Synthesis of 5- (5-amino-1,3,4-oxadiazol-2-yl) -4- Sulfonamide;

(5) 5-(5-아미노-1,3,4-옥사디아졸-2-일)-2-플루오로-4-(4-요오도-페닐아미노)-벤젠설폰아미드; 및(5) 5- (5-Amino-1,3,4-oxadiazol-2-yl) -2-fluoro-4- (4-iodo-phenylamino) - benzenesulfonamide; And

(6) 4-(5-아미노-1,3,4-옥사디아졸-2-일)-2-플루오로-5-(4-요오도-페닐아미노)-벤젠설폰아미드.(6) 4- (5-Amino-1,3,4-oxadiazol-2-yl) -2-fluoro-5- (4-iodo-phenylamino) -benzenesulfonamide.

제 2b 군Group 2b

(1) 5-(5-아미노-1,3,4-옥사디아졸-2-일)-2-플루오로-4-(4-요오도-2-메틸-페닐아미노)-벤젠설폰아미드;(1) 5- (5-amino-1,3,4-oxadiazol-2-yl) -2-fluoro-4- (4-iodo-2-methyl-phenylamino) -benzenesulfonamide;

(2) 5-(5-아미노-1,3,4-옥사디아졸-2-일)-2-플루오로-4-(4-요오도-페닐아미노)-N-메틸-N-(3-모폴린-4-일-프로필)-벤젠설폰아미드;(2) 5- (5-amino-1,3,4-oxadiazol-2-yl) -2-fluoro-4- (4-iodo-phenylamino) -Morpholin-4-yl-propyl) -benzenesulfonamide;

(3) 5-(5-아미노-1,3,4-옥사디아졸-2-일)-2,3-디플루오로-4-(4-요오도-2-메틸-페닐아미노)-벤젠설폰아미드;(3) Synthesis of 5- (5-amino-1,3,4-oxadiazol-2-yl) -2,3- difluoro-4- (4- Sulfonamide;

(4) 5-(5-아미노-1,3,4-옥사디아졸-2-일)-2-플루오로-4-(4-요오도-페닐아미노)-벤젠설폰아미드;(4) 5- (5-Amino-1,3,4-oxadiazol-2-yl) -2-fluoro-4- (4-iodo-phenylamino) - benzenesulfonamide;

(5) 5-(5-아미노-1,3,4-옥사디아졸-2-일)-4-(2-클로로-4-요오도-페닐아미노)-2,3-디플루오로-N-[3-(4-메틸-피페라진-1-일)-프로필]-벤젠설폰아미드; 및(5) 5- (5-Amino-1,3,4-oxadiazol-2-yl) -4- (2-chloro-4- iodo-phenylamino) -2,3- difluoro-N - [3- (4-methyl-piperazin-1-yl) -propyl] -benzenesulfonamide; And

(6) 5-(5-아미노-1,3,4-옥사디아졸-2-일)-4-(2-클로로-4-요오도-페닐아미노)-2-플루오로-N-(3-피페라진-1-일-프로필)-벤젠설폰아미드.(6) 5- (5-amino-1,3,4-oxadiazol-2-yl) -4- - piperazin-l-yl-propyl) -benzenesulfonamide.

제 3 군Group 3

(1) 2-플루오로-4-(4-요오도-2-메틸-페닐아미노)-5-(5-머캅토-1,3,4-옥사디아졸-2-일)-벤젠설폰아미드;(1) Synthesis of 2-fluoro-4- (4-iodo-2-methyl-phenylamino) -5- (5-mercapto-1,3,4-oxadiazol- ;

(2) 2-플루오로-5-(4-요오도-페닐아미노)-4-(5-머캅토-1,3,4-옥사디아졸-2-일)-벤젠설폰아미드;(2) 2-Fluoro-5- (4-iodo-phenylamino) -4- (5-mercapto-1,3,4-oxadiazol-2-yl) -benzenesulfonamide;

(3) 2,3-디플루오로-4-(4-요오도-2-메틸-페닐아미노)-5-(5-머캅토-1,3,4-옥사디아졸-2-일)-벤젠설폰아미드;(3) Synthesis of 2,3-difluoro-4- (4-iodo-2-methyl- phenylamino) -5- (5-mercapto-1,3,4-oxadiazol- Benzenesulfonamide;

(4) 2-플루오로-4-(4-요오도-페닐아미노)-5-(5-머캅토-1,3,4-옥사디아졸-2-일)-벤젠설폰아미드;(4) 2-Fluoro-4- (4-iodo-phenylamino) -5- (5-mercapto-1,3,4-oxadiazol-2-yl) -benzenesulfonamide;

(5) 4-(2-클로로-4-요오도-페닐아미노)-2,3-디플루오로-5-(5-머캅토-1,3,4-옥사디아졸-2-일)-벤젠설폰아미드; 및(5) 4- (2-Chloro-4-iodo-phenylamino) -2,3- difluoro-5- (5-mercapto-1,3,4-oxadiazol- Benzenesulfonamide; And

(6) 4-(2-클로로-4-요오도-페닐아미노)-2-플루오로-5-(5-머캅토-1,3,4-옥사디아졸-2-일)-벤젠설폰아미드.(6) Synthesis of 4- (2-chloro-4-iodo-phenylamino) -2-fluoro-5- (5-mercapto-1,3,4-oxadiazol- .

제 4 군Group 4

(1) 2-플루오로-5-(5-하이드록시-1,3,4-티아디아졸-2-일)-4-(4-요오도-2-메틸-페닐아미노)-벤젠설폰아미드;(1) Synthesis of 2-fluoro-5- (5-hydroxy-1,3,4-thiadiazol-2-yl) -4- (4-iodo-2- methyl- phenylamino) ;

(2) 2-플루오로-4-(5-하이드록시-1,3,4-티아디아졸-2-일)-5-(4-요오도-페닐아미 노)-벤젠설폰아미드;(2) 2-Fluoro-4- (5-hydroxy-1,3,4-thiadiazol-2-yl) -5- (4-iodo-phenylamino) -benzenesulfonamide;

(3) 2,3-디플루오로-5-(5-하이드록시-1,3,4-티아디아졸-2-일)-4-(4-요오도-2-메틸-페닐아미노)-벤젠설폰아미드;(3) 2,3-Difluoro-5- (5-hydroxy-1,3,4-thiadiazol-2-yl) -4- Benzenesulfonamide;

(4) 2-플루오로-5-(5-하이드록시-1,3,4-티아디아졸-2-일)-4-(4-요오도-페닐아미 노)-벤젠설폰아미드;(4) 2-Fluoro-5- (5-hydroxy-1,3,4-thiadiazol-2-yl) -4- (4-iodo-phenylamino) -benzenesulfonamide;

(5) 4-(2-클로로-4-요오도-페닐아미노)-2,3-디플루오로-5-(5-하이드록시-1,3,4-티아디아졸-2-일)-벤젠설폰아미드; 및(5) 4- (2-Chloro-4-iodo-phenylamino) -2,3- difluoro-5- (5-hydroxy-1,3,4-thiadiazol- Benzenesulfonamide; And

(6) 4-(2-클로로-4-요오도-페닐아미노)-2-플루오로-5-(5-하이드록시-1,3,4-티아디아졸-2-일)-벤젠설폰아미드.(6) Synthesis of 4- (2-chloro-4-iodo-phenylamino) -2-fluoro-5- (5-hydroxy-1,3,4-thiadiazol- .

제 5 군Group 5

(1) 5-(5-아미노-1,3,4-티아디아졸-2-일)-2-플루오로-4-(4-요오도-2-메틸-페닐아미노)-벤젠설폰아미드;(1) 5- (5-amino-1,3,4-thiadiazol-2-yl) -2-fluoro-4- (4-iodo-2-methyl-phenylamino) -benzenesulfonamide;

(2) 4-(5-아미노-1,3,4-티아디아졸-2-일)-5-(4-요오도-페닐아미노)-2-머캅토-벤젠설폰아미드;(2) 4- (5-amino-1,3,4-thiadiazol-2-yl) -5- (4-iodo-phenylamino) -2-mercapto-benzenesulfonamide;

(3) 5-(5-아미노-1,3,4-티아디아졸-2-일)-2,3-디플루오로-4-(4-요오도-2-메틸-페닐아미노)-벤젠설폰아미드;(3) Synthesis of 5- (5-amino-1,3,4-thiadiazol-2-yl) -2,3- difluoro-4- (4- Sulfonamide;

(4) 5-(5-아미노-1,3,4-티아디아졸-2-일)-2-플루오로-4-(4-요오도-페닐아미노)-벤젠설폰아미드;(4) 5- (5-Amino-1,3,4-thiadiazol-2-yl) -2-fluoro-4- (4-iodo-phenylamino) - benzenesulfonamide;

(5) 5-(5-아미노-1,3,4-티아디아졸-2-일)-4-(4-클로로-2-요오도-페닐아미노)-2,3-디플루오로-벤젠설폰아미드; 및(5) A mixture of 5- (5-amino-1,3,4-thiadiazol-2-yl) -4- Sulfonamide; And

(6) 5-(5-아미노-1,3,4-티아디아졸-2-일)-4-(2-클로로-4-요오도-페닐아미노)-2-플루오로-벤젠설폰아미드.(6) 5- (5-Amino-l, 3, 4-thiadiazol-2-yl) -4- (2-chloro-4- iodo-phenylamino) -2-fluoro-benzenesulfonamide.

제 6 군Group 6

(1) 2-플루오로-5-(5-하이드록시-4H-1,2,4-트리아졸-3-일)-4-(4-요오도-2-메틸-페닐아미노)-벤젠설폰아미드;(1) Synthesis of 2-fluoro-5- (5-hydroxy-4H-1,2,4-triazol- amides;

(2) 2-플루오로-4-(5-하이드록시-4H-1,2,4-트리아졸-3-일)-5-(4-요오도-페닐아미노)-벤젠설폰아미드;(2) 2-Fluoro-4- (5-hydroxy-4H-1,2,4-triazol-3-yl) -5- (4-iodo-phenylamino) -benzenesulfonamide;

(3) 2,3-디플루오로-5-(5-하이드록시-4H-1,2,4-트리아졸-3-일)-4-(4-요오도-2-메 틸-페닐아미노)-벤젠설폰아미드;(3) Synthesis of 2,3-difluoro-5- (5-hydroxy-4H-1,2,4-triazol- ) -Benzenesulfonamide;

(4) 5-[4-(2-디메틸아미노-에틸)-5-하이드록시-4H-1,2,4-트리아졸-3-일]-2-플루오로-4-(4-요오도-페닐아미노)-벤젠설폰아미드;(4) Synthesis of 5- [4- (2-dimethylamino-ethyl) -5-hydroxy-4H-1,2,4- triazol- -Phenylamino) - &lt; / RTI &gt;benzenesulfonamide;

(5) 4-(2-클로로-4-요오도-페닐아미노)-2,3-디플루오로-5-(5-하이드록시-4H-1,2,4-트리아졸-3-일)-벤젠설폰아미드; 및(5) Synthesis of 4- (2-chloro-4-iodo-phenylamino) -2,3-difluoro-5- (5- - benzenesulfonamide; And

(6) 4-(2-클로로-4-요오도-페닐아미노)-2-플루오로-5-(5-하이드록시-4-메틸-4H-1,2,4-트리아졸-3-일)-벤젠설폰아미드.(6) 4- (2-Chloro-4-iodo-phenylamino) -2-fluoro-5- (5- ) -Benzenesulfonamide. &Lt; / RTI &gt;

제 7 군Group 7

(1) 5-(5-아미노-4H-1,2,4-트리아졸-3-일)-2-플루오로-4-(4-요오도-2-메틸-페닐아미노)-벤젠설폰아미드;(1) 5- (5-Amino-4H-1,2,4-triazol-3-yl) -2-fluoro-4- (4-iodo-2-methyl- phenylamino) ;

(2) 4-(5-아미노-4H-1,2,4-트리아졸-3-일)-2-플루오로-5-(4-요오도-페닐아미노)-벤젠설폰아미드;(2) 4- (5-Amino-4H-1,2,4-triazol-3-yl) -2-fluoro-5- (4-iodo-phenylamino) -benzenesulfonamide;

(3) 5-(5-아미노-4-메틸-4H-1,2,4-트리아졸-3-일)-2,3-디플루오로-4-(4-요오도-2-메틸-페닐아미노)-벤젠설폰아미드;(3) 5- (5-Amino-4-methyl-4H-1,2,4-triazol-3-yl) -2,3- difluoro- Phenylamino) - &lt; / RTI &gt;benzenesulfonamide;

(4) 5-[5-아미노-4-(3-디메틸아미노-프로필)-4H-1,2,4-트리아졸-3-일]-2-플루오로-4-(4-요오도-페닐아미노)-벤젠설폰아미드;(4) Synthesis of 5- [5-amino-4- (3-dimethylamino-propyl) -4H-1,2,4- triazol- Phenylamino) - &lt; / RTI &gt;benzenesulfonamide;

(5) 5-(5-아미노-4H-1,2,4-트리아졸-3-일)-4-(2-클로로-4-요오도-페닐아미노)-2,3-디플루오로-벤젠설폰아미드; 및(5) 5- (5-Amino-4H-1,2,4-triazol-3-yl) -4- Benzenesulfonamide; And

(6) 5-(5-아미노-4-메틸-4H-1,2,4-트리아졸-3-일)-4-(2-클로로-4-요오도-페닐아미노)-2-플루오로-벤젠설폰아미드.(6) 5- (5-Amino-4-methyl-4H-1,2,4-triazol- -Benzenesulfonamide. &Lt; / RTI &gt;

제 8 군Group 8

(1) 2-플루오로-5-(3-하이드록시-이속사졸-5-일)-4-(4-요오도-2-메틸-페닐아미노)-벤젠설폰아미드;(1) 2-Fluoro-5- (3-hydroxy-isoxazol-5-yl) -4- (4-iodo-2-methyl-phenylamino) -benzenesulfonamide;

(2) 2-플루오로-4-(3-하이드록시-이속사졸-5-일)-5-(4-요오도-페닐아미노)-벤젠설폰아미드;(2) 2-Fluoro-4- (3-hydroxy-isoxazol-5-yl) -5- (4-iodo-phenylamino) -benzenesulfonamide;

(3) 2,3-디플루오로-5-(3-하이드록시-이속사졸-5-일)-4-(4-요오도-2-메틸-페닐아미노)-벤젠설폰아미드;(3) 2,3-Difluoro-5- (3-hydroxy-isoxazol-5-yl) -4- (4-iodo-2-methyl-phenylamino) -benzenesulfonamide;

(4) 2-플루오로-5-(3-하이드록시-이속사졸-5-일)-4-(4-요오도-페닐아미노)-벤젠설폰아미드;(4) 2-Fluoro-5- (3-hydroxy-isoxazol-5-yl) -4- (4-iodo-phenylamino) -benzenesulfonamide;

(5) 4-(2-클로로-4-요오도-페닐아미노)-2,3-디플루오로-5-(3-하이드록시-이속사졸-5-일)-벤젠설폰아미드; 및(5) 4- (2-Chloro-4-iodo-phenylamino) -2,3-difluoro-5- (3-hydroxy-isoxazol-5-yl) -benzenesulfonamide; And

(6) 4-(2-클로로-4-요오도-페닐아미노)-2-플루오로-5-(3-하이드록시-이속사졸-5-일)-벤젠설폰아미드.(6) 4- (2-Chloro-4-iodo-phenylamino) -2-fluoro-5- (3-hydroxy-isoxazol-5-yl) -benzenesulfonamide.

제 9 군Group 9

(1) 5-(3-아미노-이속사졸-5-일)-2-플루오로-4-(4-요오도-2-메틸-페닐아미노)-벤젠설폰아미드;(1) 5- (3-Amino-isoxazol-5-yl) -2-fluoro-4- (4-iodo-2-methyl-phenylamino) -benzenesulfonamide;

(2) 4-(3-아미노-이속사졸-5-일)-2-브로모-5-(4-요오도-페닐아미노)-벤젠설폰아미드;(2) 4- (3-Amino-isoxazol-5-yl) -2-bromo-5- (4-iodo-phenylamino) - benzenesulfonamide;

(3) 5-(3-아미노-이속사졸-5-일)-2,3-디플루오로-4-(4-요오도-2-메틸-페닐아미노)-벤젠설폰아미드;(3) 5- (3-Amino-isoxazol-5-yl) -2,3-difluoro-4- (4-iodo-2-methyl-phenylamino) -benzenesulfonamide;

(4) 5-(3-아미노-이속사졸-5-일)-2-플루오로-4-(4-요오도-페닐아미노)-벤젠설폰아미드;(4) 5- (3-Amino-isoxazol-5-yl) -2-fluoro-4- (4-iodo-phenylamino) -benzenesulfonamide;

(5) 5-(3-아미노-이속사졸-5-일)-4-(2-클로로-4-요오도-페닐아미노)-2,3-디플루오로-벤젠설폰아미드; 및(5) 5- (3-Amino-isoxazol-5-yl) -4- (2-chloro-4-iodo-phenylamino) -2,3-difluoro-benzenesulfonamide; And

(6) 5-(3-아미노-이속사졸-5-일)-4-(2-클로로-4-요오도-페닐아미노)-2-플루오로-벤젠설폰아미드.(6) 5- (3-Amino-isoxazol-5-yl) -4- (2-chloro-4- iodo-phenylamino) -2-fluoro-benzenesulfonamide.

제 10 군Group 10

(1) 2-플루오로-4-(4-요오도-2-메틸-페닐아미노)-5-(3-머캅토-이속사졸-5-일)-벤젠설폰아미드;(1) 2-Fluoro-4- (4-iodo-2-methyl-phenylamino) -5- (3-mercapto-isoxazol-5-yl) -benzenesulfonamide;

(2) 4-(2-클로로-4-요오도-페닐아미노)-2-플루오로-5-(3-머캅토-이속사졸-5-일)-벤젠설폰아미드;(2) 4- (2-Chloro-4-iodo-phenylamino) -2-fluoro-5- (3-mercapto-isoxazol-5-yl) -benzenesulfonamide;

(3) 2,3-디플루오로-4-(4-요오도-2-메틸-페닐아미노)-5-(3-머캅토-이속사졸-5-일)-벤젠설폰아미드;(3) 2,3-Difluoro-4- (4-iodo-2-methyl-phenylamino) -5- (3-mercapto-isoxazol-5-yl) -benzenesulfonamide;

(4) 4-(2-클로로-4-요오도-페닐아미노)-2,3-디플루오로-5-(3-머캅토-이속사졸-5-일)-벤젠설폰아미드;(4) 4- (2-Chloro-4-iodo-phenylamino) -2,3-difluoro-5- (3-mercapto-isoxazol-5-yl) -benzenesulfonamide;

(5) 2-플루오로-4-(4-요오도-페닐아미노)-5-(3-머캅토-이속사졸-5-일)-벤젠설폰아미드; 및(5) 2-Fluoro-4- (4-iodo-phenylamino) -5- (3-mercapto-isoxazol-5-yl) -benzenesulfonamide; And

(6) 2-브로모-5-(4-요오도-페닐아미노)-4-(3-머캅토-이속사졸-5-일)-벤젠설폰아미드(6) To a solution of 2-bromo-5- (4-iodo-phenylamino) -4- (3-mercapto-isoxazol-

제 11 군Group 11

(1) 2-플루오로-5-(3-하이드록시-이속사졸-4-일)-4-(4-요오도-2-메틸-페닐아미노)-벤젠설폰아미드;(1) 2-Fluoro-5- (3-hydroxy-isoxazol-4-yl) -4- (4-iodo-2-methyl-phenylamino) -benzenesulfonamide;

(2) 4-(2-클로로-4-요오도-페닐아미노)-2-플루오로-5-(3-하이드록시-이속사졸-4-일)-벤젠설폰아미드;(2) 4- (2-Chloro-4-iodo-phenylamino) -2-fluoro-5- (3-hydroxy-isoxazol-4-yl) -benzenesulfonamide;

(3) 2,3-플루오로-5-(3-하이드록시-이속사졸-4-일)-4-(4-요오도-2-메틸-페닐아미노)-벤젠설폰아미드;(3) 2,3-Fluoro-5- (3-hydroxy-isoxazol-4-yl) -4- (4-iodo-2-methyl-phenylamino) -benzenesulfonamide;

(4) 4-(2-클로로-4-요오도-페닐아미노)-2,3-디플루오로-5-(3-하이드록시-이속사졸-4-일)-벤젠설폰아미드;(4) 4- (2-Chloro-4-iodo-phenylamino) -2,3-difluoro-5- (3-hydroxy-isoxazol-4-yl) -benzenesulfonamide;

(5) 2-플루오로-5-(3-하이드록시-이속사졸-4-일)-4-(4-요오도-페닐아미노)-벤젠설폰아미드; 및(5) 2-Fluoro-5- (3-hydroxy-isoxazol-4-yl) -4- (4-iodo-phenylamino) -benzenesulfonamide; And

(6) 2-브로모-4-(3-하이드록시-이속사졸-4-일)-5-(4-요오도-페닐아미노)-벤젠설폰아미드.(6) 2-Bromo-4- (3-hydroxy-isoxazol-4-yl) -5- (4-iodo-phenylamino) -benzenesulfonamide.

제 12 군Group 12

(1) 5-(3-아미노-이속사졸-4-일)-2-플루오로-4-(4-요오도-2-메틸-페닐아미노)-벤젠설폰아미드;(1) 5- (3-Amino-isoxazol-4-yl) -2-fluoro-4- (4-iodo-2-methyl-phenylamino) -benzenesulfonamide;

(2) 5-(3-아미노-이속사졸-4-일)-4-(2-클로로-4-요오도-페닐아미노)-2-플루오로-벤젠설폰아미드;(2) 5- (3-Amino-isoxazol-4-yl) -4- (2-chloro-4-iodo-phenylamino) -2-fluoro-benzenesulfonamide;

(3) 5-(3-아미노-이속사졸-4-일)-2,3-디플루오로-4-(4-요오도-2-메틸-페닐아미노)-벤젠설폰아미드;(3) 5- (3-Amino-isoxazol-4-yl) -2,3-difluoro-4- (4-iodo-2-methyl-phenylamino) -benzenesulfonamide;

(4) 5-(3-아미노-이속사졸-4-일)-4-(2-클로로-4-요오도-페닐아미노)-2,3-디플루오로-벤젠설폰아미드;(4) 5- (3-Amino-isoxazol-4-yl) -4- (2-chloro-4-iodo-phenylamino) -2,3-difluoro-benzenesulfonamide;

(5) 5-(3-아미노-이속사졸-4-일)-2-플루오로-4-(4-요오도-페닐아미노)-벤젠설폰아미드; 및(5) 5- (3-Amino-isoxazol-4-yl) -2-fluoro-4- (4-iodo-phenylamino) -benzenesulfonamide; And

(6) 4-(3-아미노-이속사졸-4-일)-2-클로로-5-(4-요오도-페닐아미노)-벤젠설폰아미드.(6) 4- (3-Amino-isoxazol-4-yl) -2-chloro-5- (4-iodo-phenylamino) -benzenesulfonamide.

제 13 군Group 13

(1) 5-(3-아미노-이속사졸-4-일)-2-플루오로-4-(4-요오도-2-메틸-페닐아미노)-벤젠설폰아미드;(1) 5- (3-Amino-isoxazol-4-yl) -2-fluoro-4- (4-iodo-2-methyl-phenylamino) -benzenesulfonamide;

(2) 5-(3-아미노-이속사졸-4-일)-4-(2-클로로-4-요오도-페닐아미노)-2-플루오로-벤젠설폰아미드;(2) 5- (3-Amino-isoxazol-4-yl) -4- (2-chloro-4-iodo-phenylamino) -2-fluoro-benzenesulfonamide;

(3) 5-(3-아미노-이속사졸-4-일)-2,3-디플루오로-4-(4-요오도-2-메틸-페닐아미노)-벤젠설폰아미드;(3) 5- (3-Amino-isoxazol-4-yl) -2,3-difluoro-4- (4-iodo-2-methyl-phenylamino) -benzenesulfonamide;

(4) 5-(3-아미노-이속사졸-4-일)-4-(2-클로로-4-요오도-페닐아미노)-2,3-디플루오로-벤젠설폰아미드;(4) 5- (3-Amino-isoxazol-4-yl) -4- (2-chloro-4-iodo-phenylamino) -2,3-difluoro-benzenesulfonamide;

(5) 5-(3-아미노-이속사졸-4-일)-2-플루오로-4-(4-요오도-페닐아미노)-벤젠설폰아미드; 및(5) 5- (3-Amino-isoxazol-4-yl) -2-fluoro-4- (4-iodo-phenylamino) -benzenesulfonamide; And

(6) 4-(3-아미노-이속사졸-4-일)-2-클로로-5-(4-요오도-페닐아미노)-벤젠설폰아미드.(6) 4- (3-Amino-isoxazol-4-yl) -2-chloro-5- (4-iodo-phenylamino) -benzenesulfonamide.

제 14 군Group 14

(1) 5-(2-아미노-5H-피롤-3-일)-2-플루오로-4-(4-요오도-2-메틸-페닐아미노)-벤젠설폰아미드;(1) 5- (2-Amino-5H-pyrrol-3-yl) -2-fluoro-4- (4-iodo-2-methyl-phenylamino) -benzenesulfonamide;

(2) 5-(2-아미노-5H-피롤-3-일)-4-(2-클로로-4-요오도-페닐아미노)-2-플루오로-벤젠설폰아미드;(2) 5- (2-Amino-5H-pyrrol-3-yl) -4- (2-chloro-4-iodo-phenylamino) -2-fluoro-benzenesulfonamide;

(3) 5-(2-아미노-5H-피롤-3-일)-2,3-디플루오로-4-(4-요오도-2-메틸-페닐아미노)-벤젠설폰아미드;(3) 5- (2-Amino-5H-pyrrol-3-yl) -2,3-difluoro-4- (4-iodo-2-methyl-phenylamino) -benzenesulfonamide;

(4) 5-(2-아미노-5H-피롤-3-일)-4-(2-클로로-4-요오도-페닐아미노)-2,3-디플루오 로-벤젠설폰아미드;(4) 5- (2-Amino-5H-pyrrol-3-yl) -4- (2-chloro-4-iodo-phenylamino) -2,3-difluoro-benzenesulfonamide;

(5) 5-(2-아미노-5H-피롤-3-일)-2-플루오로-4-(4-요오도-페닐아미노)-벤젠설폰아미드; 및(5) 5- (2-Amino-5H-pyrrol-3-yl) -2-fluoro-4- (4-iodo-phenylamino) -benzenesulfonamide; And

(6) 4-(2-아미노-5H-피롤-3-일)-2-클로로-5-(4-요오도-페닐아미노)-벤젠설폰아미드.(6) 4- (2-Amino-5H-pyrrol-3-yl) -2-chloro-5- (4-iodo-phenylamino) -benzenesulfonamide.

제 15 군Group 15

(1) 2-플루오로-5-(5-하이드록시-1-메틸-1H-피라졸-4-일)-4-(4-요오도-2-메틸-페닐아미노)-벤젠설폰아미드;(1) 2-Fluoro-5- (5-hydroxy-1-methyl-1H-pyrazol-4-yl) -4- (4-iodo-2-methyl-phenylamino) -benzenesulfonamide;

(2) 4-(2-클로로-4-요오도-페닐아미노)-2-플루오로-5-(5-하이드록시-1H-피라졸-4-일)-벤젠설폰아미드;(2) 4- (2-Chloro-4-iodo-phenylamino) -2-fluoro-5- (5-hydroxy-1H-pyrazol-4-yl) -benzenesulfonamide;

(3) 2,3-디플루오로-5-(5-하이드록시-1H-피라졸-4-일)-4-(4-요오도-2-메틸-페닐아미노)-벤젠설폰아미드;(3) 2,3-Difluoro-5- (5-hydroxy-1H-pyrazol-4-yl) -4- (4-iodo-2-methyl-phenylamino) -benzenesulfonamide;

(4) 4-(2-클로로-4-요오도-페닐아미노)-2,3-디플루오로-5-(5-하이드록시-1H-피라 졸-4-일)-벤젠설폰아미드;(4) 4- (2-Chloro-4-iodo-phenylamino) -2,3-difluoro-5- (5-hydroxy-1H-pyrazol-4-yl) -benzenesulfonamide;

(5) 2-플루오로-5-[5-하이드록시-1-[3-(4-메틸-피페라진-1-일)-프로필]-1H-피라졸-4-일]-4-(4-요오도-페닐아미노)-벤젠설폰아미드; 및(5) Synthesis of 2-fluoro-5- [5- hydroxy-1- [3- (4-methyl-piperazin- 4-iodo-phenylamino) -benzenesulfonamide; And

(6) 2-플루오로-4-(5-하이드록시-1H-피라졸-4-일)-5-(4-요오도-페닐아미노)-벤젠설폰아미드.(6) 2-Fluoro-4- (5-hydroxy-1H-pyrazol-4-yl) -5- (4-iodo-phenylamino) -benzenesulfonamide.

제 16 군Group 16

(1) 2-플루오로-5-(5-하이드록시-3-메틸-3H-1,2,3-트리아졸-4-일)-4-(4-요오도-2-메틸-페닐아미노)-벤젠설폰아미드;(1) Synthesis of 2-fluoro-5- (5-hydroxy-3-methyl-3H-1,2,3-triazol- ) -Benzenesulfonamide;

(2) 4-(2-클로로-4-요오도-페닐아미노)-2-플루오로-5-(5-하이드록시-3H-1,2,3-트리아졸-4-일)-벤젠설폰아미드;(2-chloro-4-iodo-phenylamino) -2-fluoro-5- (5-hydroxy- amides;

(3) 2,3-디플루오로-5-(5-하이드록시-3H-1,2,3-트리아졸-4-일)-4-(4-요오도-2-메 틸-페닐아미노)-벤젠설폰아미드;(3) Synthesis of 2,3-difluoro-5- (5-hydroxy-3H-1,2,3-triazol- ) -Benzenesulfonamide;

(4) 4-(2-클로로-4-요오도-페닐아미노)-2,3-디플루오로-5-(5-하이드록시-3H-1,2,3-트리아졸-4-일)-벤젠설폰아미드;(4-chloro-4-iodo-phenylamino) -2,3-difluoro-5- (5-hydroxy- - benzenesulfonamide;

(5) 2-플루오로-5-(5-하이드록시-3H-1,2,3-트리아졸-4-일)-4-(4-요오도-페닐아미노)-벤젠설폰아미드; 및(5) 2-Fluoro-5- (5-hydroxy-3H-1,2,3-triazol-4-yl) -4- (4-iodo-phenylamino) -benzenesulfonamide; And

(6) 2-플루오로-5-[5-하이드록시-3-[2-(2-메톡시-에톡시)-에틸]-3H-1,2,3-트리아 졸-4-일]-4-(4-요오도-페닐아미노)-벤젠설폰아미드.(6) Synthesis of 2-fluoro-5- [5- hydroxy-3- [2- (2-methoxy-ethoxy) 4- (4-Iodo-phenylamino) -benzenesulfonamide.

제 17 군Group 17

(1) 2-플루오로-5-(5-하이드록시-3-메틸-3H-1,2,3-트리아졸-4-일)-4-(4-요오도-2-메틸-페닐아미노)-벤젠설폰아미드;(1) Synthesis of 2-fluoro-5- (5-hydroxy-3-methyl-3H-1,2,3-triazol- ) -Benzenesulfonamide;

(2) 4-(2-클로로-4-요오도-페닐아미노)-2-플루오로-5-(5-하이드록시-3H-1,2,3-트리아졸-4-일)-벤젠설폰아미드;(2-chloro-4-iodo-phenylamino) -2-fluoro-5- (5-hydroxy- amides;

(3) 2,3-디플루오로-5-(5-하이드록시-3H-1,2,3-트리아졸-4-일)-4-(4-요오도-2-메 틸-페닐아미노)-벤젠설폰아미드;(3) Synthesis of 2,3-difluoro-5- (5-hydroxy-3H-1,2,3-triazol- ) -Benzenesulfonamide;

(4) 4-(2-클로로-4-요오도-페닐아미노)-2,3-디플루오로-5-(5-하이드록시-3H-1,2,3-트리아졸-4-일)-벤젠설폰아미드;(4-chloro-4-iodo-phenylamino) -2,3-difluoro-5- (5-hydroxy- - benzenesulfonamide;

(5) 2-플루오로-5-(5-하이드록시-3H-1,2,3-트리아졸-4-일)-4-(4-요오도-페닐아미노)-벤젠설폰아미드; 및(5) 2-Fluoro-5- (5-hydroxy-3H-1,2,3-triazol-4-yl) -4- (4-iodo-phenylamino) -benzenesulfonamide; And

(6) 2-플루오로-5-[5-하이드록시-3-[2-(2-메톡시-에톡시)-에틸]-3H-1,2,3-트리아 졸-4-일]-4-(4-요오도-페닐아미노)-벤젠설폰아미드.(6) Synthesis of 2-fluoro-5- [5- hydroxy-3- [2- (2-methoxy-ethoxy) 4- (4-Iodo-phenylamino) -benzenesulfonamide.

제 18 군Group 18

(1) 2-플루오로-4-(4-요오도-2-메틸-페닐아미노)-5-(5-옥소-4,5-디하이드로-테트라졸-1-일)-벤젠설폰아미드;(1) 2-Fluoro-4- (4-iodo-2-methyl-phenylamino) -5- (5-oxo-4,5-dihydro-tetrazol-1-yl) -benzenesulfonamide;

(2) 4-(2-클로로-4-요오도-페닐아미노)-2-플루오로-5-(5-옥소-4,5-디하이드로-테트라졸-1-일)-벤젠설폰아미드;(2) 4- (2-Chloro-4-iodo-phenylamino) -2-fluoro-5- (5-oxo-4,5-dihydro-tetrazol-1-yl) -benzenesulfonamide;

(3) 2,3-디플루오로-4-(4-요오도-2-메틸-페닐아미노)-5-(5-옥소-4,5-디하이드로-테트라졸-1-일)-벤젠설폰아미드;(3) Synthesis of 2,3-difluoro-4- (4-iodo-2-methyl-phenylamino) -5- (5-oxo-4,5-dihydro-tetrazol- Sulfonamide;

(4) 4-(2-클로로-4-요오도-페닐아미노)-2,3-디플루오로-5-(5-옥소-4,5-디하이드로-테트라졸-1-일)-벤젠설폰아미드;(4) Synthesis of 4- (2-chloro-4-iodo-phenylamino) -2,3-difluoro-5- (5-oxo-4,5-dihydro-tetrazol- Sulfonamide;

(5) 2-플루오로-4-(4-요오도-페닐아미노)-5-(5-옥소-4,5-디하이드로-테트라졸-1-일)-벤젠설폰아미드; 및(5) 2-Fluoro-4- (4-iodo-phenylamino) -5- (5-oxo-4,5-dihydro-tetrazol-1-yl) -benzenesulfonamide; And

(6) 2,6-디플루오로-3-(4-요오도-페닐아미노)-4-(5-옥소-4,5-디하이드로-테트라졸-1-일)-벤젠설폰아미드.(6) 2,6-Difluoro-3- (4-iodo-phenylamino) -4- (5-oxo-4,5-dihydro-tetrazol-l-yl) -benzenesulfonamide.

제 19 군Group 19

(1) 2-플루오로-4-(4-요오도-2-메틸-페닐아미노)-5-(4-메틸-5-옥소-4,5-디하이드 로-테트라졸-1-일)-벤젠설폰아미드;(4-methyl-5-oxo-4,5-dihydro-tetrazol-1-yl) - benzenesulfonamide;

(2) 4-(2-클로로-4-요오도-페닐아미노)-2-플루오로-5-(4-메틸-5-옥소-4,5-디하이드로-테트라졸-1-일)-벤젠설폰아미드;(2-chloro-4-iodo-phenylamino) -2-fluoro-5- (4-methyl- Benzenesulfonamide;

(3) 2,3-디플루오로-4-(4-요오도-2-메틸-페닐아미노)-5-(5-옥소-4,5-디하이드로-테트라졸-1-일)-벤젠설폰아미드;(3) Synthesis of 2,3-difluoro-4- (4-iodo-2-methyl-phenylamino) -5- (5-oxo-4,5-dihydro-tetrazol- Sulfonamide;

(4) 4-(2-클로로-4-요오도-페닐아미노)-2,3-디플루오로-5-(5-옥소-4,5-디하이드로-테트라졸-1-일)-벤젠설폰아미드;(4) Synthesis of 4- (2-chloro-4-iodo-phenylamino) -2,3-difluoro-5- (5-oxo-4,5-dihydro-tetrazol- Sulfonamide;

(5) 5-[4-(2-디메틸아미노-에틸)-5-옥소-4,5-디하이드로-테트라졸-1-일]-2-플루오로-4-(4-요오도-페닐아미노)-벤젠설폰아미드; 및(5) Synthesis of 5- [4- (2-dimethylamino-ethyl) -5-oxo-4,5-dihydro-tetrazol- Amino) -benzenesulfonamide; And

(6) 2-플루오로-5-(4-요오도-페닐아미노)-4-(4-메틸-5-옥소-4,5-디하이드로-테트라졸-1-일)-벤젠설폰아미드.(6) 2-Fluoro-5- (4-iodo-phenylamino) -4- (4-methyl-5-oxo-4,5-dihydro-tetrazol-1-yl) -benzenesulfonamide.

제 20 군Group 20

(1) 2-플루오로-4-(4-요오도-2-메틸-페닐아미노)-5-(2-옥소-2,3-디하이드로-1,2,3,5-옥사티아디아졸-4-일)-벤젠설폰아미드;(1) Synthesis of 2-fluoro-4- (4-iodo-2-methyl- phenylamino) -5- (2-oxo-2,3-dihydro-1,2,3,5-oxathiadiazole -4-yl) - &lt; / RTI &gt;benzenesulfonamide;

(2) 4-(2-클로로-4-요오도-페닐아미노)-2-플루오로-5-(2-옥소-2,3-디하이드로-1,2,3,5-옥사티아디아졸-4-일)-벤젠설폰아미드;(2) Synthesis of 4- (2-chloro-4-iodo-phenylamino) -2-fluoro-5- (2-oxo-2,3-dihydro-1,2,3,5-oxathiadiazole -4-yl) - &lt; / RTI &gt;benzenesulfonamide;

(3) 2,3-디플루오로-4-(4-요오도-2-메틸-페닐아미노)-5-(2-옥소-2,3-디하이드로-1,2,3,5-옥사티아디아졸-4-일)-벤젠설폰아미드;(3) Synthesis of 2,3-difluoro-4- (4-iodo-2-methyl-phenylamino) -5- (2-oxo-2,3- Thiadiazol-4-yl) -benzenesulfonamide;

(4) 4-(2-클로로-4-요오도-페닐아미노)-2,3-디플루오로-5-(2-옥소-2,3-디하이드로-1,2,3,5-옥사티아디아졸-4-일)-벤젠설폰아미드;(4) Synthesis of 4- (2-chloro-4-iodo-phenylamino) -2,3- difluoro-5- (2-oxo-2,3-dihydro- Thiadiazol-4-yl) -benzenesulfonamide;

(5) 2-플루오로-4-(4-요오도-페닐아미노)-5-(2-옥소-2,3-디하이드로-1,2,3,5-옥사티아디아졸-4-일)-벤젠설폰아미드; 및(5) Synthesis of 2-fluoro-4- (4-iodo-phenylamino) -5- (2-oxo-2,3-dihydro-1,2,3,5-oxathiadiazol- ) -Benzenesulfonamide; And

(6) 2-플루오로-5-(4-요오도-페닐아미노)-4-(2-옥소-2,3-디하이드로-1,2,3,5-옥사티아디아졸-4-일)-벤젠설폰아미드.(6) Synthesis of 2-fluoro-5- (4-iodo-phenylamino) -4- (2-oxo-2,3-dihydro-1,2,3,5-oxathiadiazol- ) -Benzenesulfonamide. &Lt; / RTI &gt;

제 21 군Group 21

(1) 2-플루오로-4-(4-요오도-2-메틸-페닐아미노)-5-(3-메틸-2-옥소-2,3-디하이드 로-1,2,3,5-옥사티아디아졸-4-일)-벤젠설폰아미드;(1) 2- fluoro-4- (4-iodo-2-methyl-phenylamino) -5- (3-methyl-2-oxo-2,3-dihydro- - oxathiadiazol-4-yl) - benzenesulfonamide;

(2) 2,6-디플루오로-3-(4-요오도-페닐아미노)-4-(3-메틸-2-옥소-2,3-디하이드로-1,2,3,5-옥사티아디아졸-4-일)-벤젠설폰아미드;(2) Synthesis of 2,6-difluoro-3- (4-iodo-phenylamino) -4- (3-methyl-2-oxo-2,3-dihydro- Thiadiazol-4-yl) -benzenesulfonamide;

(3) 2,3-디플루오로-4-(4-요오도-2-메틸-페닐아미노)-5-(3-메틸-2-옥소-2,3-디하이드로-1,2,3,5-옥사티아디아졸-4-일)-벤젠설폰아미드;(3) 2,3-Difluoro-4- (4-iodo-2-methyl-phenylamino) -5- (3-methyl- , 5-oxathiadiazol-4-yl) -benzenesulfonamide;

(4) 2-플루오로-4-(4-요오도-페닐아미노)-5-(3-메틸-2-옥소-2,3-디하이드로-1,2,3,5-옥사티아디아졸-4-일)-벤젠설폰아미드;(4) Synthesis of 2-fluoro-4- (4-iodo-phenylamino) -5- (3-methyl-2-oxo-2,3-dihydro-1,2,3,5-oxathiadiazole -4-yl) - &lt; / RTI &gt;benzenesulfonamide;

(5) 4-(2-클로로-4-요오도-페닐아미노)-2,3-디플루오로-5-(3-메틸-2-옥소-2,3-디하이드로-1,2,3,5-옥사티아디아졸-4-일)-벤젠설폰아미드; 및(5) 4- (2-Chloro-4-iodo-phenylamino) -2,3-difluoro-5- (3-methyl- , 5-oxathiadiazol-4-yl) -benzenesulfonamide; And

(6) 4-(2-클로로-4-요오도-페닐아미노)-2-플루오로-N-메틸-5-(3-메틸-2-옥소-2,3-디하이드로-1,2,3,5-옥사티아디아졸-4-일)-벤젠설폰아미드.(6) 4- (2-Chloro-4-iodo-phenylamino) -2-fluoro-N- 3,5-oxathiadiazol-4-yl) -benzenesulfonamide.

제 22 군Group 22

(1) 2-플루오로-4-(4-요오도-2-메틸-페닐아미노)-5-(5-옥소-2,5-디하이드로-이속사졸-3-일)-벤젠설폰아미드;(1) 2-Fluoro-4- (4-iodo-2-methyl-phenylamino) -5- (5-oxo-2,5-dihydro-isoxazol-3-yl) -benzenesulfonamide;

(2) 2,6-디플루오로-3-(4-요오도-페닐아미노)-4-(5-옥소-2,5-디하이드로-이속사졸-3-일)-벤젠설폰아미드;(2) 2,6-Difluoro-3- (4-iodo-phenylamino) -4- (5-oxo-2,5-dihydro-isoxazol-3-yl) -benzenesulfonamide;

(3) 2,3-디플루오로-4-(4-요오도-2-메틸-페닐아미노)-5-(5-옥소-2,5-디하이드로-이속사졸-3-일)-벤젠설폰아미드;(3) Synthesis of 2,3-difluoro-4- (4-iodo-2-methyl-phenylamino) -5- Sulfonamide;

(4) 2-플루오로-4-(4-요오도-페닐아미노)-5-(5-옥소-2,5-디하이드로-이속사졸-3-일)-벤젠설폰아미드;(4) 2-Fluoro-4- (4-iodo-phenylamino) -5- (5-oxo-2,5-dihydro-isoxazol-3-yl) -benzenesulfonamide;

(5) 4-(2-클로로-4-요오도-페닐아미노)-2,3-디플루오로-5-(5-옥소-2,5-디하이드로-이속사졸-3-일)-벤젠설폰아미드; 및(5) Preparation of 4- (2-chloro-4-iodo-phenylamino) -2,3-difluoro-5- (5-oxo-2,5- dihydro- Sulfonamide; And

(6) 4-(2-클로로-4-요오도-페닐아미노)-2-디플루오로-5-(5-옥소-2,5-디하이드로-이속사졸-3-일)-벤젠설폰아미드.(6) Synthesis of 4- (2-chloro-4-iodo-phenylamino) -2-difluoro-5- (5-oxo-2,5- dihydro-isoxazol- .

제 23 군Group 23

(1) 5-[6-(4-요오도-2-메틸-페닐아미노)-1H-벤즈이미다졸-5-일]-1,3,4-옥사디아졸-2-올;(1) 5- [6- (4-Iodo-2-methyl-phenylamino) -1H-benzimidazol-5-yl] -1,3,4-oxadiazol-2-ol;

(2) 5-[6-(4-요오도-페닐아미노)-벤조푸란-5-일]-1,3,4-옥사디아졸-2-올;(2) 5- [6- (4-Iodo-phenylamino) -benzofuran-5-yl] -1,3,4-oxadiazol-2-ol;

(3) 5-[7-플루오로-6-(4-요오도-2-메틸-페닐아미노)-벤족사졸-5-일]-1,3,4-옥사디아졸-2-올;(3) 5- [7-Fluoro-6- (4-iodo-2-methyl-phenylamino) -benzooxazol-5-yl] -1,3,4-oxadiazol-2-ol;

(4) 5-[5-(4-요오도-페닐아미노)-벤조푸란-6-일]-1,3,4-옥사디아졸-2-올;(4) 5- [5- (4-Iodo-phenylamino) -benzofuran-6-yl] -1,3,4-oxadiazol-2-ol;

(5) 5-[6-(2-클로로-4-요오도-페닐아미노)-7-플루오로-1,3-디하이드로-이소벤조푸란-5-일]-1,3,4-옥사디아졸-2-올; 및(5) 5- [6- (2-Chloro-4-iodo-phenylamino) -7-fluoro-1,3-dihydro-isobenzofuran- Diazol-2-ol; And

(6) 5-[6-(2-클로로-4-요오도-페닐아미노)-1-메틸-1H-벤즈이미다졸-5-일]-1,3,4-옥사디아졸-2-올.(6) Synthesis of 5- [6- (2-chloro-4-iodo-phenylamino) -1-methyl-1H- benzimidazol-5-yl] -1,3,4-oxadiazol- .

제 24 군Group 24

(1) 5-[2-아미노-6-(4-요오도-2-메틸-페닐아미노)-1H-벤즈이미다졸-5-일]-1,3,4-옥사디아졸-2-올;(1) Synthesis of 5- [2-amino-6- (4-iodo-2-methyl-phenylamino) -1H-benzimidazol-5-yl] -1,3,4-oxadiazol- ;

(2) 5-[6-(4-요오도-페닐아미노)-벤조[b]티오펜-5-일]-1,3,4-옥사디아졸-2-올;(2) 5- [6- (4-Iodo-phenylamino) -benzo [b] thiophen-5-yl] -1,3,4-oxadiazol-2-ol;

(3) 5-[7-플루오로-6-(4-요오도-2-메틸-페닐아미노)-벤조티아졸-5-일]-1,3,4-옥사디아졸-2-올;(3) 5- [7-Fluoro-6- (4-iodo-2-methyl-phenylamino) -benzothiazol-5-yl] -1,3,4-oxadiazol-2-ol;

(4) 5-[5-(4-요오도-페닐아미노)-벤조[b]티오펜-5-일]-1,3,4-옥사디아졸-2-올;(4) 5- [5- (4-Iodo-phenylamino) -benzo [b] thiophen-5-yl] -1,3,4-oxadiazol-2-ol;

(5) 5-[6-(2-클로로-4-요오도-페닐아미노)-7-플루오로-1,3-디하이드로-벤조[c]티오펜-5-일]-1,3,4-옥사디아졸-2-올; 및(5) 5- [6- (2-Chloro-4-iodo-phenylamino) -7-fluoro-1,3-dihydro-benzo [c] thiophen- 4-oxadiazol-2-ol; And

(6) 5-[6-(2-클로로-4-요오도-페닐아미노)-2-옥소-2,3-디하이드로-1H-2$I＞4_-2,1,3-벤조티아디아졸-5-일]-1,3,4-옥사디아졸-2-올.(6) Synthesis of 5- [6- (2-chloro-4-iodo-phenylamino) -2-oxo-2,3-dihydro-1H- 5-yl] -1,3,4-oxadiazol-2-ol.

제 25 군Group 25

(1) 5-[2-아미노-6-(4-요오도-2-메틸-페닐아미노)-벤조티아졸-5-일]-1,3,4-옥사디아졸-2-올;(1) 5- [2-Amino-6- (4-iodo-2-methyl-phenylamino) -benzothiazol-5-yl] -1,3,4-oxadiazol-2-ol;

(2) 5-[6-(4-요오도-페닐아미노)-1H-인돌-5-일]-1,3,4-옥사디아졸-2-올;(2) 5- [6- (4-Iodo-phenylamino) -lH-indol-5-yl] -1,3,4-oxadiazol-2-ol;

(3) 5-[7-플루오로-6-(4-요오도-2-메틸-페닐아미노)-벤조티아졸-5-일]-1,3,4-옥사디아졸-2-올;(3) 5- [7-Fluoro-6- (4-iodo-2-methyl-phenylamino) -benzothiazol-5-yl] -1,3,4-oxadiazol-2-ol;

(4) 5-[5-(4-요오도-페닐아미노)-1H-인돌-6-일]-1,3,4-옥사디아졸-2-올;(4) 5- [5- (4-Iodo-phenylamino) -1H-indol-6-yl] -1,3,4-oxadiazol-2-ol;

(5) 5-[6-(2-클로로-4-요오도-페닐아미노)-7-플루오로-2,3-디하이드로-1H-이소인 돌-5-일]-1,3,4-옥사디아졸-2-올; 및(5) 5- [6- (2-Chloro-4-iodo-phenylamino) -7-fluoro-2,3-dihydro-1H-isoindol-5-yl] Oxadiazol-2-ol; And

(6) 5-[5-(2-클로로-4-요오도-페닐아미노)-1H-인다졸-6-일]-1,3,4-옥사디아졸-2-올.(6) 5- [5- (2-Chloro-4-iodo-phenylamino) -1H-indazol-6-yl] -1,3,4-oxadiazol-2-ol.

제 26 군Group 26

(1) 5-[2-아미노-6-(4-요오도-2-메틸-페닐아미노)-벤조티아졸-5-일]-1,3,4-옥사디아졸-2-올;(1) 5- [2-Amino-6- (4-iodo-2-methyl-phenylamino) -benzothiazol-5-yl] -1,3,4-oxadiazol-2-ol;

(2) 5-[6-(4-요오도-페닐아미노)-1H-인돌-5-일]-1,3,4-옥사디아졸-2-올;(2) 5- [6- (4-Iodo-phenylamino) -lH-indol-5-yl] -1,3,4-oxadiazol-2-ol;

(3) 5-[7-플루오로-6-(4-요오도-2-메틸-페닐아미노)-벤조티아졸-5-일]-1,3,4-옥사디아졸-2-올;(3) 5- [7-Fluoro-6- (4-iodo-2-methyl-phenylamino) -benzothiazol-5-yl] -1,3,4-oxadiazol-2-ol;

(4) 5-[5-(4-요오도-페닐아미노)-벤족사졸-6-일]-1,3,4-옥사디아졸-2-올;(4) 5- [5- (4-Iodo-phenylamino) -benzoxazol-6-yl] -1,3,4-oxadiazol-2-ol;

(5) 5-[6-(2-클로로-4-요오도-페닐아미노)-7-플루오로-2,3-디하이드로-1H-이소인 돌-5-일]-1,3,4-옥사디아졸-2-올; 및(5) 5- [6- (2-Chloro-4-iodo-phenylamino) -7-fluoro-2,3-dihydro-1H-isoindol-5-yl] Oxadiazol-2-ol; And

(6) 5-[5-(2-클로로-4-요오도-페닐아미노)-1H-인다졸-6-일]-1,3,4-옥사디아졸-2-올.(6) 5- [5- (2-Chloro-4-iodo-phenylamino) -1H-indazol-6-yl] -1,3,4-oxadiazol-2-ol.

C. 합성C. Synthesis

개시된 화합물은 하기 반응식 1 내지 25 또는 그와 유사한 변형된 방법에 따라 합성될 수 있다. 이들 합성 전략은 하기 실시예 1 내지 8에 추가로 예시된다. 반응식 1에서, 화합물(4)과 화합물(5) 사이의 용매는 톨루엔이다(PhMe).The disclosed compounds can be synthesized according to the following Reaction Schemes 1 to 25 or a similar method analogous thereto. These synthetic strategies are further exemplified in the following Examples 1 to 8. In Scheme 1, the solvent between compound (4) and compound (5) is toluene (PhMe).

D. 사용D. use

개시된 화합물은, 발명의 요약 부분에서 제시된 바와 같이, 신경병증성 동통을 포함하는 만성 동통과 관련된 질환 또는 증상뿐만 아니라 MEK 캐스케이드에 의해 조절되는 질환 또는 증상의 예방법 및 치료법 둘다에 유용하다. 예를 들면, 한 실시태양에서, 개시된 방법은 수술후 동통, 환지통(phantom limb pain), 작열 동통, 통풍, 삼차신경통(trigeminal neuralgia), 급성 포진 및 포진후 동통, 작열통, 당뇨병성 신경병증, 플렉서스 어벌젼, 신경종, 혈관염, 압궤 손상, 수축 손상, 조직 손상, 수술후 동통, 관절통 또는 사지 절단과 관련되어 있다.The disclosed compounds are useful in both the prevention and treatment of diseases or conditions associated with chronic pain including neuropathic pain as well as diseases or conditions modulated by MEK cascades as well as diseases or conditions associated with chronic pain, as set forth in the Summary of the Invention. For example, in one embodiment, the disclosed methods are useful for treating post-operative pain, phantom limb pain, burning pain, gout, trigeminal neuralgia, acute herpes and postherpetic pain, burning pain, diabetic neuropathy, Neuralgia, vasculitis, crush injury, contraction injury, tissue damage, postoperative pain, arthralgia, or limb amputation.

예를 들면, 국부 손상은 국부 또는 국소 투여에 의해 치료될 수 있다. 전신에 영향을 미치는 만성 동통(예: 당뇨병성 신경병증)은 개시된 조성물의 (주사 또는 경구를 통한) 전신계 투여에 의해 치료될 수 있다. 하체에 국한된 만성 동통(예: 수술후 동통)을 위한 치료는 중추적, 예를 들어 경막외로 투여될 수 있다. 제제화 및 투여 방법은 하나 이상의 MEK 억제제, 또는 MEK 억제제 및 다른 약학 제제, 예를 들어 소염제, 진통제, 근육 이완제 또는 항감염제의 조합의 사용을 포함할 수 있다. 바람직한 투여 경로로는 경구, 수막강내 또는 경막외, 피하내, 정맥내, 근육내가 있고, 인간 이외의 포유동물의 경우에는 발바닥내, 바람직하게는 경막외가 있다.For example, local injury can be treated by local or topical administration. Chronic pain affecting the whole body (such as diabetic neuropathy) can be treated by systemic administration (via injection or oral) of the disclosed compositions. Treatment for chronic lower back pain (eg, post-operative pain) may be pivotal, eg, epidural. Formulations and methods of administration may include the use of one or more MEK inhibitors, or combinations of MEK inhibitors and other pharmaceutical agents, such as anti-inflammatory, analgesic, muscle relaxants or anti-infective agents. Preferred routes of administration are oral, submucosal or epidural, subcutaneous, intravenous, intramuscular, and in the case of non-human mammals, in the sole, preferably epidural.

1. 투여량1. Dose

당해 기술분야의 숙련자들은, 공지된 방법에 따라, 연령, 체중, 일반적인 건강상태, 치료가 필요한 동통의 유형 및 다른 약물의 존재와 같은 인자들을 고려하여 환자를 위한 적합한 투여량을 결정할 수 있을 것이다. 일반적으로, 효과량은 매일 0.1 내지 1000mg/체중kg, 바람직하게는 1 내지 300 mg/체중kg이고, 1일 투여량은 보통 체중의 성인의 경우 10 내지 5000mg일 것이다. 100mg, 200mg, 300mg 또는 400mg의 시판되는 캡슐 또는 다른 제제(예: 액체 및 피막 정제)를 개시된 방법에 따라 투여할 수 있다.Those skilled in the art will be able, depending on the known methods, to determine suitable dosages for a patient considering factors such as age, body weight, general health conditions, the type of pain required to be treated and the presence of other drugs. Generally, the effective amount will be from 0.1 to 1000 mg / kg of body weight per day, preferably from 1 to 300 mg / kg of body weight per day, and the daily dose will be from 10 to 5000 mg for adults of normal body weight. 100 mg, 200 mg, 300 mg or 400 mg of a commercially available capsule or other agent (such as a liquid and a coating tablet) may be administered according to the disclosed methods.

2. 제제화2. Formulation

투여 단위 형태는 정제, 캡슐, 환약, 분말, 과립, 경구용 수성 및 비수성 용액 및 현탁액, 개별적인 투여량으로 세분하도록 개조된 용기에 팩킹된 비경구용 용액을 포함한다. 또한, 투여 단위 형태는 조절된 방출 제제(예: 피하내 이식)를 포함하는 다양한 투여 방법에 적합하게 변형될 수 있다. 투여 방법은 경구, 직장, 비경구(정맥내, 근육내, 피하내), 조내(intracisternal), 질내, 복강내, 소포내,국부(점적(drop), 분말, 연고, 겔 또는 크림) 및 흡입(협측 또는 비강내 분무)에 의한 것을 포함한다.Dosage unit forms include parenteral solutions packaged in tablets, capsules, pills, powders, granules, aqueous and non-aqueous solutions and suspensions for oral, subdivided into individual doses. In addition, dosage unit forms may be adapted to various modes of administration, including controlled release formulations (e.g., subcutaneous implants). Methods of administration include, but are not limited to, oral, rectal, parenteral (intravenous, intramuscular, subcutaneous), intracisternal, intravaginal, intraperitoneal, intratracheal, local (drop, powder, ointment, (Buccal or intranasal spray).

비경구 제제는 약학적으로 허용가능한 수성 또는 비수성 용액, 분산액, 현탁액, 유화액 및 이들의 제조를 위한 무균 분말을 포함한다. 담체의 예로는 물, 에탄올, 폴리올(프로필렌 글리콜, 폴리에틸렌 글리콜), 식물성 오일 및 주사가능한 유기 에스테르(예: 에틸 올레에이트)가 포함된다. 코팅물(예: 레시틴), 계면활성제의 사용, 또는 적합한 입자 크기를 유지시킴으로써 유동성이 유지될 수 있다. 고체 투여 형태를 위한 담체는 (a) 충전재 또는 증량제, (b) 결합제, (c) 습윤제, (d) 붕괴제, (e) 용액 응결지연제, (f) 흡수 촉진제, (g) 흡착제, (h) 윤활제, (i) 완충제 및 (j) 추진제를 포한다.Parenteral formulations include pharmaceutically acceptable aqueous or nonaqueous solutions, dispersions, suspensions, emulsions and sterile powders for their manufacture. Examples of carriers include water, ethanol, polyols (propylene glycol, polyethylene glycol), vegetable oils and injectable organic esters such as ethyl oleate. Fluidity can be maintained by the use of coatings (such as lecithin), the use of surfactants, or by maintaining a suitable particle size. The carrier for the solid dosage form may be selected from the group consisting of (a) fillers or extenders, (b) binders, (c) wetting agents, (d) disintegrators, (e) solution coagulation retarders, (f) absorption promoters, h) lubricants, (i) buffering agents and (j) propellants.

또한, 조성물은 보존화제, 습윤제, 유화제 및 분산제와 같은 보조제; 파라벤, 클로로부탄올, 페놀 및 소르브산과 같은 항균제; 설탕 또는 염화나트륨과 같은 등장성 제제; 알루미늄 모노스테아레이트 및 젤라틴과 같은 흡수-연장제 (absorption-prolonging agent); 및 흡착-개선제를 함유할 수 있다.The compositions may also contain adjuvants such as preserving agents, wetting agents, emulsifying agents and dispersing agents; Antimicrobial agents such as parabens, chlorobutanol, phenol and sorbic acid; Isotonic agents such as sugar or sodium chloride; Absorption-prolonging agents such as aluminum monostearate and gelatin; And adsorption-enhancing agents.

3. 관련 화합물3. Related compounds

본 발명은, 개시된 화합물 및 개시된 화합물과 밀접하게 관련된 약학적으로 허용가능한 형태, 예를 들어 이들의 염, 에스테르, 아미드, 수화물 또는 용매화된 형태; 마스킹되거나 보호된 형태; 및 라세믹 혼합물 또는 거울이성질적으로 또는 광학적으로 순수한 형태를 제공한다.The invention also relates to the disclosed compounds and their pharmaceutically acceptable forms, for example their salts, esters, amides, hydrates or solvated forms, which are closely related to the disclosed compounds; Masked or protected form; And racemic mixtures or mirrors provide a heterogeneously or optically pure form.

약학적으로 허용가능한 염, 에스테르 및 아미드는, 적당한 유익/유해 비율내에 속하고, 약리학적으로 효과적이고, 과도한 독성, 자극 또는 알레르기 반응없이 환자의 조직과 접촉하는데 적합한 카복실레이트 염(예: C1-8알킬, 사이클로알킬, 아릴, 헤테로아릴 또는 비-방향족 헤테로사이클릭), 아미드산 부가 염, 에스테르 및 아미드를 포함한다. 대표적인 염으로는 하이드로브로마이드, 하이드로클로라이드, 설페이트, 비설페이트, 니트레이트, 아세테이트, 옥살레이트, 발레레이트, 올레에이트, 팔미테이트, 스테아레이트, 라우레이트, 보레이트, 벤조에이트, 락테이트, 포스페이트, 토실레이트, 시트레이트, 말레에이트, 푸마레이트, 숙시네이트, 타르트레이트, 나프틸레이트, 메실레이트, 글루코헵토네이트, 락티오비오네이트 및 라우릴설포네이트가 포함된다. 이들은 알칼리 금속 및 알칼리토 양이온, 예를 들어 나트륨, 칼륨, 칼슘 및 마그네슘 뿐만 아니라 비독성 암모늄, 4급 암모늄, 및 아민 양이온, 예를 들어 테트라메틸 암모늄, 메틸아민, 트리메틸아민 및 에틸아민을 포함할 수 있다. 예를 들면, 본원에 참고로 인용되는 에스. 엠. 베르게(S. M. Berge) 등의 문헌["Pharmaceutical Salts",J. Pharm. Sci., 1977, 66:1-19]을 참조한다. 본 발명의 대표적인 약학적으로 허용가능한 아미드로는 암모니아, 1급 C1-6알킬 아민 및 2급 디(C1-6알킬) 아민으로부터 유도된 것들을 포함한다. 2급 아민으로는 하나 이상의 질소원자 및 선택적으로 1 내지 2개의 추가의 헤테로원자를 함유한 5원 또는 6원 헤테로사이클릭 또는 헤테로방향족 고리 잔기가 포함된다. 바람직한 아미드는 암모니아, C1-3알킬 1급 아민, 디(C1-2알킬)아민으로부터 유도된다. 본 발명의 대표적인 약학적으로 허용가능한 에스테르로는 C1-7알킬, C5-7사이클로알킬, 페닐 및 페닐(C1-6)알킬 에스테르가 포함된다. 바람직한 에스테르로는 메틸 에스테르가 포함된다.Pharmaceutically acceptable salts, esters and amides fall within the appropriate benefit / harmful ratios and are pharmacologically effective and include carboxylate salts suitable for contacting the tissues of a patient without undue toxicity, irritation or allergic response, such as C 1 -8- alkyl, cycloalkyl, aryl, heteroaryl or non-aromatic heterocyclic), amide acid addition salts, esters and amides. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate , Citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactothiobionate and laurylsulfonate. These include alkali metal and alkaline earth cations such as sodium, potassium, calcium and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations such as tetramethylammonium, methylamine, trimethylamine and ethylamine . See, for example, S. M. SM Berge et al . , &Quot; Pharmaceutical Salts &quot;, J. Pharm. Sci. , 1977, 66: 1-19. Representative pharmaceutically acceptable amides of the present invention include those derived from ammonia, primary C 1-6 alkylamines and secondary di (C 1-6 alkyl) amines. The secondary amine includes a 5- or 6-membered heterocyclic or heteroaromatic ring moiety containing one or more nitrogen atoms and optionally 1 to 2 additional heteroatoms. Preferred amides are derived from ammonia, C 1-3 alkyl primary amines, di (C 1-2 alkyl) amines. Representative pharmaceutically acceptable esters of the present invention include C 1-7 alkyl, C 5-7 cycloalkyl, phenyl and phenyl (C 1-6 ) alkyl esters. Preferred esters include methyl esters.

또한, 본 발명은 보호기에 의해 마스킹된 하나 이상의 작용기(예: 하이드록실, 아미노 또는 카복실)를 갖는 개시된 화합물을 포함한다. 이러한 마스킹되거나 보호된 화합물의 몇몇은 약학적으로 허용가능하다; 다른 것들은 중간체로서 유용할 것이다. 본 발명에 개시된 합성 중간체 및 방법, 및 기타 이들의 변형물 및 변형된 방법도 또한 본 발명의 범위내에 속한다.The invention also encompasses the disclosed compounds with one or more functional groups masked by a protecting group (e.g., hydroxyl, amino or carboxyl). Some of these masked or protected compounds are pharmaceutically acceptable; Others will be useful as intermediates. Synthetic intermediates and methods disclosed herein, and other variations and modifications thereof, are also within the scope of the present invention.

하이드록실 보호기Hydroxyl protecting group

하이드록실 보호기로는 에테르, 에스테르, 및 1,2- 및 1,3-디올을 위한 보호기가 포함된다. 에테르 보호기로는 메틸, 치환된 메틸 에테르, 치환된 에틸 에테르, 치환된 벤질 에테르, 실릴 에테르 및 실리 에테르의 다른 작용기로의 전환체가 포함된다.Hydroxyl protecting groups include ethers, esters, and protecting groups for 1,2- and 1,3-diols. Ether protecting groups include methyl, substituted methyl ethers, substituted ethyl ethers, substituted benzyl ethers, silyl ethers, and the conversion of silyl ether to other functional groups.

치환된 메틸 에테르Substituted methyl ether

치환된 메틸 에테르로는 메톡시메틸, 메틸티오메틸, t-우틸티오메틸, (페닐디메틸실릴) 메톡시메틸, 벤질옥시메틸, p-에톡시벤질옥시메틸, (4-메톡시페녹시)메틸, 구아이아콜메틸, t-부톡시메틸, 4-펜테닐옥시메틸, 실록시메틸, 2-메톡시에톡시메틸, 2,2,2-트리클로로에톡시메틸, 비스(2-클로로-에톡시)메틸, 2-(트리메틸실릴)에톡시메틸, 테트라하이드로피라닐, 3-브로모테트라하이드로-피라닐, 테트라하이드로티오피라닐, 1-메톡시사이클로헥실, 4-메톡시테트라하이드로피라닐, 4-메톡시테트라하이드로티오-피라닐, 4-메톡시테트라하이드로티오피라닐, S,S-디옥시도, 1-[(2-클로로-4-메틸)페닐]-4-메톡시피페리딘-4-일, 1,4-디옥산-2-일, 테트라하이드로푸라닐, 테트라하이드로티오푸라닐 및 2,3,3a,4,5,6,7,7a-옥타하이드로-7,8,8-트리메틸-4,7-에타노벤조푸란-2-일이 포함된다.Examples of the substituted methyl ether include methoxymethyl, methylthiomethyl, t-butylthiomethyl, (phenyldimethylsilyl) methoxymethyl, benzyloxymethyl, p-ethoxybenzyloxymethyl, (4-methoxyphenoxy) methyl , 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, bis (2-chloro-ethoxy) methyl, t-butoxymethyl, Methoxycyclohexyl, 4-methoxytetrahydropyranyl, tetrahydrothiopyranyl, 3-bromotetrahydro-pyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl , 4-methoxytetrahydrothio-pyranyl, 4-methoxytetrahydrothiopyranyl, S, S-dioxido, 1 - [(2-chloro-4-methyl) phenyl] -4- methoxypiper 4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiopyranyl and 2,3,3a, 4,5,6,7,7a-octahydro-7,8 , 8-trimethyl-4,7-ethanobenzofuran-2-yl do.

치환된 에틸 에테르Substituted ethyl ether

치환된 에틸 에테르로는 1-에톡시에틸, 1-(2-클로로에톡시)에틸, 1-메틸-1-메톡시에틸, 1-메틸-1-벤질옥시에틸, 1-메틸-1-벤질옥시-2-플루오로에틸, 2,2,2-트리클로로에틸, 2-트리메틸실릴에틸, 2-(페닐셀레닐)에틸, t-부틸, 알릴, p-클로로페닐, p-메톡시페닐, 2,4-디니트로페닐 및 벤질이 포함된다.Examples of substituted ethyl ethers are 1-ethoxyethyl, 1- (2-chloroethoxy) ethyl, 1-methyl-1-methoxyethyl, 2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2- (phenylselenyl) ethyl, t-butyl, allyl, p- chlorophenyl, p- 2,4-dinitrophenyl, and benzyl.

치환된 벤질 에테르Substituted benzyl ether

치환된 벤질 에테르로는 p-메톡시벤질, 3,4-디메톡시벤질, o-니트로벤질, p-니트로벤질, p-할로벤질, 2,6-디클로로벤질, p-시아노벤질, p-페닐벤질, 2- 및 4-피콜릴, 3-메틸-2-피콜릴 N-옥시도, 디페닐메틸, p,p'-디니트로벤즈하이드릴, 5-디벤조수베릴, 트리페닐메틸, α-나프틸디페닐-메틸, p-메톡시페닐디페닐메틸, 디(p-메톡시페닐)페닐메틸, 트리-(p-메톡시페닐)메틸, 4-(4'-브로모펜아실옥시)페닐디페닐메틸, 4,4',4"-트리스(4,5-디클로로프탈리미도페닐)메틸, 4,4',4"-트리스(레불리노일옥시페닐)메틸, 4,4',4"-트리스(벤조일옥시페닐)메틸, 3-(이미다졸-1-일메틸)비스(4',4"-디메톡시페닐)-메틸, 1,1-비스(4-메톡시페닐)-1'-피레닐메틸, 9-안트릴, 9-(9-페닐)크산테닐, 9-(9-페닐-10-옥소)-안트릴, 1,3-벤조디티올란-2-일 및벤즈이소티아졸릴 S,S-디옥시도가 포함된다.Substituted benzyl ethers include p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, Phenylbenzyl, 2- and 4-picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl, p, p'- dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, (p-methoxyphenyl) methyl, 4- (4'-bromophenacyloxy) methyl, p-methoxyphenyldiphenylmethyl, 4,4 ', 4 "-tris (levulinoyloxyphenyl) methyl, 4,4', 4" -tris (4,5-dichloropthalimidophenyl) Bis (4-methoxyphenyl) -methyl, 1,1-bis (4-methoxyphenyl) (9-phenyl-10-oxo) -anthryl, 1,3-benzodithiolan-2-yl, and Benzisothiazolyl S, S-dioxido.

실릴 에테르Silyl ether

실릴 에테르로는 트리메틸실릴, 트리에틸실릴, 트리이소프로필실릴, 디메틸이소프로필실릴, 디에틸이소프로필실릴, 디메틸텍실실릴, t-부틸디메틸실릴, t-부틸디페닐실릴, 트리벤질실릴, 트리-p-크실릴실릴, 트리페닐실릴, 디페닐메틸실릴, 및 t-부틸메톡시페닐실릴이 포함된다.Examples of the silyl ether include trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethyltetoxysilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl, p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl, and t-butylmethoxyphenylsilyl.

에스테르류Esters

에스테르류 보호기로는 에스테르, 카보네이트, 보조 분해(assisted cleavage), 기타 에스테르 및 설포네이트가 포함된다.Ester protecting groups include esters, carbonates, assisted cleavage, other esters and sulfonates.

에스테르ester

보호 에스테르의 예로는 포르메이트, 벤조일포르메이트, 아세테이트, 클로로아세테이트, 디클로로아세테이트, 트리클로로아세테이트, 트리플루오로아세테이트, 메톡시아세테이트, 트리페닐메톡시아세테이트, 페녹시아세테이트, p-클로로페녹시아세테이트, p-P-페닐아세테이트, 3-페닐프로피오네이트, 4-옥소펜타노에이트(레불리네이트), 4,4-(에틸렌디티오)펜타노에이트, 피발로에이트, 아다만토에이트, 크로토네이트, 4-메톡시크로토네이트, 벤조에이트, p-페닐벤조에이트 및 2,4,6-트리메틸벤조에이트(메시토에이트)가 포함된다.Examples of protective esters include formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, p-phenyl acetate, 3-phenyl propionate, 4-oxopentanoate (levulinate), 4,4- (ethylene dithio) pentanoate, pivaloate, adamantate, crotonate, 4-methoxy crotonate, benzoate, p-phenyl benzoate and 2,4,6-trimethyl benzoate (mesoate).

카보네이트Carbonate

카보네이트의 예로는 메틸, 9-플루오레닐메틸, 에틸, 2,2,2-트리클로로에틸, 2-(트리메틸실릴)에틸, 2-(페닐설포닐) 에틸, 2-(트리페닐포스포니오) 에틸, 이소부틸, 비닐, 알릴, p-니트로페닐, 벤질, p-메톡시벤질, 3,4-디메톡시벤질, o-니트로벤질, p-니트로벤질, S-벤질 티오카보네이트, 4-에톡시-1-나프틸 및 메틸 디티오카보네이트가 포함된다.Examples of the carbonate include methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2- (trimethylsilyl) ethyl, 2- (phenylsulfonyl) ethyl, 2- (triphenylphosphonyl Benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, S-benzylthiocarbonate, 4- 1-naphthyl, and methyl dithiocarbonate.

보조 분해Secondary decomposition

보조 분해 보호기의 예로는 2-요오도벤조에이트, 4-아지도-부티레이트, 4-니트로-4-메틸펜타노에이트, o-(디브로모메틸) 벤조에이트, 2-포르밀벤젠-설포네이트, 2-(메틸티오메톡시) 에틸 카보네이트, 4-(메틸티오메톡시메틸) 벤조에이트, 및 2-(메틸티오메톡시메틸) 벤조에이트가 포함된다.Examples of secondary decomposition protecting groups include 2-iodobenzoate, 4-azido-butyrate, 4-nitro-4-methyl pentanoate, o- (dibromomethyl) benzoate, 2-formylbenzene- , 2- (methylthiomethoxy) ethyl carbonate, 4- (methylthiomethoxymethyl) benzoate, and 2- (methylthiomethoxymethyl) benzoate.

기타 에스테르Other esters

상기 부류 이외에, 기타 에스테르로는 2,6-디클로로-4-메틸펜옥시아세테이트, 2,6-디클로로-4-(1,1,3,3-테트라메틸부틸)펜옥시아세테이트, 2,4-비스(1,1-디메틸프로필)페녹시아세테이트, 클로로디페닐아세테이트, 이소부티레이트, 모노숙시노에이트, (E)-2-메틸-2-부테노에이트(티글로에이트), o-(메톡시카보닐) 벤조에이트, p-P-벤조에이트, α-나프토에이트, 니트레이트, 알킬 N,N,N',N'-테트라메틸포스포로디아미데이트, N-페닐카바메이트, 보레이트, 디메틸포스피노티오닐 및 2,4-디니트로페닐설페네이트가 포함된다.In addition to the above classes, other esters include 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4- (1,1,3,3-tetramethylbutyl) phenoxyacetate, 2,4- (E) -2-methyl-2-butenoate (thioglyoate), o- (methoxyphenylacetate), chlorophenylacetate, isobutyrate, Carbonyl) benzoate, pP-benzoate, alpha -naphthoate, nitrate, alkyl N, N, N ', N'-tetramethylphosphorodiamidate, N-phenylcarbamate, borate, dimethylphosphino Thionyl and 2,4-dinitrophenylsulphonate.

설포네이트Sulfonate

보호 설포네이트로는 설페이트, 메탄설포네이트(메실레이트), 벤질설포네이트 및 토실레이트가 포함된다.Protective sulfonates include sulfate, methanesulfonate (mesylate), benzylsulfonate and tosylate.

1,2- 및 1,3-디올을 위한 보호Protection for 1,2- and 1,3-diols

1,2- 및 1,3-디올기를 위한 보호로는 사이클릭 아세탈 및 케탈, 사이클릭 오르토 에스테르 및 실릴 유도체가 포함된다.Protecting groups for the 1,2- and 1,3-diol groups include cyclic acetals and ketals, cyclic ortho esters and silyl derivatives.

사이클릭 아세탈 및 케탈Cyclic acetals and ketals

사이클릭 아세탈 및 케탈로는 메틸렌, 에틸리덴, 1-t-부틸에틸리덴, 1-페닐에틸리덴, (4-메톡시페닐)에틸리덴, 2,2,2-트리클로로에틸리덴, 아세토나이드(이소프로필리덴), 사이클로펜틸리덴, 사이클로헥실리덴, 사이클로헵틸리덴, 벤질리덴, p-메톡시벤질리덴, 2,4-디메톡시벤질리덴, 3,4-디메톡시벤질리덴 및 2-니트로벤질리덴이 포함된다.Cyclic acetals and ketals are exemplified by methylene, ethylidene, 1-t-butylethylidene, 1-phenylethylidene, (4-methoxyphenyl) ethylidene, 2,2,2-trichloroethylidene, But are not limited to, acetonide (isopropylidene), cyclopentylidene, cyclohexylidene, cycloheptylidene, benzylidene, p-methoxybenzylidene, 2,4-dimethoxybenzylidene, And 2-nitrobenzyliden.

사이클릭 오르토 에스테르Cyclic orthoester

사이클릭 오르토 에스테르로는 메톡시메틸렌, 에톡시메틸렌, 디메톡시메틸렌, 1-메톡시에틸리덴, 1-에톡시에틸리딘, 1,2-디메톡시에틸리덴, α-메톡시벤질리덴, 1-(N,N-디메틸아미노)에틸리덴 유도체, α-(N,N-디메틸아미노)벤질리덴 유도체 및 2-옥사사이클로펜틸리덴이 포함된다.Examples of the cyclic orthoester include methoxymethylene, ethoxymethylene, dimethoxymethylene, 1-methoxyethylidene, 1-ethoxyethylidene, 1,2-dimethoxyethylidene, , 1- (N, N-dimethylamino) ethylidene derivatives,? - (N, N-dimethylamino) benzylidene derivatives and 2-oxacyclopentylidene.

카복실기를 위한 보호Protection for carboxyl groups

에스테르류Esters

에스테르 보호기로는 에스테르, 치환된 메틸 에스테르, 2-치환된 에틸 에스테르, 치환된 벤질 에스테르, 실릴 에스테르, 활성화된 에스테르, 기타 유도체 및 스태닐 에스테르가 포함된다.Esters protecting groups include esters, substituted methyl esters, 2-substituted ethyl esters, substituted benzyl esters, silyl esters, activated esters, other derivatives and stannyl esters.

치환된 메틸 에스테르Substituted methyl ester

치환된 메틸 에스테르로는 9-플루오레닐메틸, 메톡시메틸, 메틸티오메틸, 테트라하이드로피라닐, 테트라하이드로푸라닐, 메톡시에톡시메틸, 2-(트리메틸실릴)에톡시-메틸, 벤질옥시메틸, 펜아실, p-브로모펜아실, α-메틸펜아실, p-메톡시펜아실, 카복스아미도메틸 및 N-프탈이미도메틸이 포함된다.Substituted methyl esters include 9-fluorenylmethyl, methoxymethyl, methylthiomethyl, tetrahydropyranyl, tetrahydrofuranyl, methoxyethoxymethyl, 2- (trimethylsilyl) ethoxy-methyl, benzyloxy Methyl, phenacyl, p-bromophenacyl, alpha -methylphenacyl, p-methoxyphenacyl, carboxamidomethyl and N-phthalimidomethyl.

2-치환된 에틸 에스테르The 2-substituted ethyl ester

2-치환된 에틸 에스테르로는 2,2,2-트리클로로에틸, 2-할로에틸, 2-클로로알킬, 2-(트리메틸실릴)에틸, 2-메틸티오에틸, 1,3-디티아닐-2-메틸, 2-(p-니트로페닐설페닐)-에틸, 2-(p-톨루엔설포닐)에틸, 2-(2'-피리딜)에틸, 2-(디페닐포스피노)에틸, 1-메틸-1-페닐에틸, t-부틸, 사이클로펜틸, 사이클로헥실, 알릴, 3-부텐-1-일, 4-(트리메틸실릴)-2-부텐-1-일, 신나밀, α-메틸신나밀, 페닐, p-(메틸머캅토)-페닐, 및 벤질이 포함된다.2-substituted ethyl esters include 2,2,2-trichloroethyl, 2-haloethyl, 2-chloroalkyl, 2- (trimethylsilyl) ethyl, 2- methylthioethyl, Methyl, 2- (p-nitrophenylsulfanyl) ethyl, 2- (p-toluenesulfonyl) ethyl, 2- Methyl-1-phenylethyl, t-butyl, cyclopentyl, cyclohexyl, allyl, 3-butene-1-yl, 4- (trimethylsilyl) , Phenyl, p- (methylmercapto) -phenyl, and benzyl.

치환된 벤질 에스테르Substituted benzyl esters

치환된 벤질 에스테르로는 트리페닐메틸, 디페닐메틸, 비스(o-니트로페닐)메틸, 9-안트릴메틸, 2-(9,10-디옥소)안트릴메틸, 5-디벤조-수베릴, 1-피레닐메틸, 2-(트리플루오로메틸)-6-크로밀메틸, 2,4,6-트리메틸벤질, p-브로모벤질, o-니트로벤질, p-니트로벤질, p-메톡시벤질, 2,6-디메톡시벤질, 4-(메틸설피닐)벤질, 4-설포벤질, 피페로닐 및 4-P-벤질이 포함된다.Examples of substituted benzyl esters include triphenylmethyl, diphenylmethyl, bis (o-nitrophenyl) methyl, 9-anthrylmethyl, 2- (9,10-dioxo) anthrylmethyl, , P-bromobenzyl, p-nitrobenzyl, p-nitrobenzyl, p-methylbenzyl, p-toluenesulfonyl, Benzyl, 2,6-dimethoxybenzyl, 4- (methylsulfinyl) benzyl, 4-sulfobenzyl, piperonyl and 4-P-benzyl.

실릴 에스테르Silyl ester

실릴 에스테르로는 트리메틸실릴, 트리에틸실릴, t-부틸디메틸실릴, i-프로필디메틸실릴, 페닐디메틸실릴 및 디-t-부틸메틸실릴이 포함된다.Silyl esters include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, i-propyldimethylsilyl, phenyldimethylsilyl and di-t-butylmethylsilyl.

기타 유도체Other derivatives

기타 유도체로는 옥사졸, 2-알킬-1,3-옥사졸린, 4-알킬-5-옥소-1,3-옥사졸리딘, 5-알킬-4-옥소-1,3-디옥솔란, 오르토 에스테르, 페닐기 및 펜타아미노코발트 (III) 착체가 포함된다.Other derivatives include oxazole, 2-alkyl-1,3-oxazoline, 4-alkyl-5-oxo-1,3-oxazolidine, 5-alkyl- Ester, phenyl group, and pentanamino cobalt (III) complex.

스태닐 에스테르Stanyl ester

스태닐 에스테르의 예로는 트리에틸스태닐 및 트리-n-부틸스태닐이 포함된다.Examples of stannyl esters include triethylstannyl and tri-n-butylstannyl.

아미드 및 하이드라자이드Amides and hydrazides

아미드로는 N,N-디메틸, 피롤리디닐, 피페리디닐, 5,6-디하이드로펜안트리디닐, o-니트로아닐라이드, N-7-니트로인돌릴, N-8-니트로-1,2,3,4-테트라하이드로퀴놀릴 및 p-P-벤젠설폰아미드가 포함된다. 하이드라자이드로는 N-페닐, N,N'-디이소프로필 및 기타 디알킬 하이드라자이드가 포함된다.The amide may be N, N-dimethyl, pyrrolidinyl, piperidinyl, 5,6-dihydrophenanthridinyl, o-nitroanilide, N-7-nitroindolyl, N-8- , 3,4-tetrahydroquinolyl, and pP-benzenesulfonamide. Hydrazazide includes N-phenyl, N, N'-diisopropyl and other dialkylhydrazides.

아미노기를 위한 보호Protection for amino groups

카바메이트류Carbamates

카바메이트류로는 카바메이트, 치환된 에틸, 보조 분해, 광분해성 분해, 우레아형 유도체, 및 기타 카바메이트가 포함된다.The carbamates include carbamates, substituted ethyl, subsidiary decomposition, photolytic decomposition, urea type derivatives, and other carbamates.

카바메이트Carbamate

카바메이트로는 메틸 및 에틸, 9-플루오레닐메틸, 9-(2-설포)플루오레닐메틸, 9-(2,7-디브로모)플루오레닐메틸, 2,7-디-t-부틸-[9-(10,10-디옥소-10,10,10,10-테트라하이드로-티옥산틸)]메틸 및 4-메톡시펜아실이 포함된다.Examples of carbamates include methyl and ethyl, 9-fluorenylmethyl, 9- (2-sulfo) fluorenylmethyl, 9- (2,7-dibromo) fluorenylmethyl, 2,7- -Butyl- [9- (10,10-dioxo-10,10,10,10-tetrahydro-thioxanthyl)] methyl and 4-methoxyphenacyl.

치환된 에틸Substituted ethyl

치환된 에틸 보호기로는 2,2,2-트리클로로에틸, 2-트리메틸실릴에틸, 2-페닐에틸, 1-(1-아다만틸)-1-메틸에틸, 1,1-디메틸-2-할로에틸, 1,1-디메틸-2,2-디브로모에틸, 1,1-디메틸-2,2,2-트리클로로에틸, 1-메틸-1-(4-비페닐일)에틸, 1-(3,5-디-t-부틸페닐)-1-메틸에틸, 2-(2'- 및 4'-피리딜)에틸, 2-(N,N-사이클로헥실카복스아미도)-에틸, t-부틸, 1-아다만틸, 비닐, 알릴, 1-이소프로필알릴, 콘아밀, 4-니트로신나밀, 퀴놀릴, N-하이드록시피페리디닐, 알킬디티오, 벤질, p-메톡시벤질, p-니트로벤질, p-브로모벤질, p-클로로벤질, 2,4-디클로로벤질, 4-메틸설피닐벤질, 9-안트릴메틸 및 디페닐메틸이 포함된다.Examples of the substituted ethyl protecting group include 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-phenylethyl, 1- (1-adamantyl) Methyl-1- (4-biphenylyl) ethyl, 1, 1-dimethyl-2,2,2-trichloroethyl, Ethyl, 2- (N, N-cyclohexylcarboxamido) -ethyl (2-methylphenyl) , t-butyl, 1-adamantyl, vinyl, allyl, 1-isopropylallyl, coneamyl, 4-nitrocinnamyl, quinolyl, N-hydroxypiperidinyl, alkyldithio, benzyl, Benzyl, p-nitrobenzyl, p-bromobenzyl, p-chlorobenzyl, 2,4-dichlorobenzyl, 4-methylsulfinylbenzyl, 9-anthrylmethyl and diphenylmethyl.

보조 분해Secondary decomposition

보조 분해를 통한 보호로는 2-메틸티오에틸, 2-메틸설포닐에틸, 2-(p-톨루엔설포닐)에틸, [2-(1,3-디티아닐)]메틸, 4-메틸티오페닐, 2,4-디메틸-티오페닐, 2-포스포니오에틸, 2-트리페닐포스포니오이소프로필, 1,1-디메틸-2-시아노에틸, m-클로로-p-아실옥시벤질, p-(디하이드록시보릴)벤질, 5-벤즈이속사졸릴-메틸 및 2-(트리플루오로메틸)-6-크로모닐메틸이 포함된다.Examples of the protecting group through the secondary decomposition include 2-methylthioethyl, 2-methylsulfonylethyl, 2- (p-toluenesulfonyl) ethyl, [2- (1,3-dithianyl)] methyl, , 2,4-dimethyl-thiophenyl, 2-phosphonioethyl, 2-triphenylphosphonioisopropyl, 1,1-dimethyl-2-cyanoethyl, m- (Dihydroxyboryl) benzyl, 5-benzisoxazolyl-methyl and 2- (trifluoromethyl) -6-chromonylmethyl.

광분해성 분해Photolytic degradation

광분해성 분해 방법은 m-니트로페닐, 3,5-디메톡시벤질, o-니트로벤질, 3,4-디메톡시-6-니트로벤질 및 페닐(o-니트로페닐)메틸과 같은 기들을 사용한다.Photolytic degradation methods use groups such as m-nitrophenyl, 3,5-dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl and phenyl (o-nitrophenyl) methyl.

우레아형 유도체Urea-type derivative

우레아형 유도체의 예로는 페노티아지닐-(10)-카보닐 유도체, N'-p-톨루엔설포닐아미노카보닐 및 N'-페닐아미노티오카보닐이 포함된다.Examples of urea-type derivatives include phenothiazinyl- (10) -carbonyl derivatives, N'-p-toluenesulfonylaminocarbonyl and N'-phenylaminothiocarbonyl.

기타 카바메이트Other carbamates

상기 이외에, 기타 카바메이트로는 t-아밀, S-벤질, 티오카바메이트, p-시아노벤질, 사이클로부틸, 사이클로헥실, 사이클로펜틸, 사이클로프로필메틸, p-데실옥시-벤질, 디이소프로필메틸, 2,2-디메톡시카보닐비닐, o-(N,N-디메틸-카복스아미도)-벤질, 1,1-디메틸-3-(N,N-디메틸카복스아미도)프로필, 1,1-디메틸-프로피닐, 디-(2-피리딜)메틸, 2-푸라닐메틸, 2-요오도에틸, 이소보르닐, 이소부틸, 이소니코티닐, p-(p'-메톡시페닐-아조)벤질, 1-메틸사이클로부틸, 1-메틸사이클로헥실, 1-메틸-1-사이클로프로필-메틸, 1-메틸-(3,5-디메톡시페닐)에틸, 1-메틸-1-(p-헤닐아조페닐)-에틸, 1-메틸-1-페닐에틸, 1-메틸-1-(4-피리딜)에틸, 페닐, p-(페닐아조)벤질, 2,4,6-트리-t-부틸페닐, 4-(트리메틸암모늄)벤질 및 2,4,6-트리메틸벤질이 포함된다.In addition to the above, other carbamates include t-amyl, S-benzyl, thiocarbamate, p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropylmethyl, Methyl, 2,2-dimethoxycarbonylvinyl, o- (N, N-dimethyl-carboxamido) -benzyl, 1,1-dimethyl- 3- (N, N- dimethylcarboxamido) Iso-butyl, isonicotinyl, p- (p'-methoxy (meth) acryloyloxy, Methyl-1-cyclopropylmethyl, 1-methyl- (3,5-dimethoxyphenyl) ethyl, 1-methyl- (4-pyridyl) ethyl, phenyl, p- (phenylazo) benzyl, 2,4,6-tri t-butylphenyl, 4- (trimethylammonium) benzyl and 2,4,6-trimethylbenzyl.

아미드류Amidule

아미드amides

아미드로는 N-포르밀, N-아세틸, N-클로로아세틸, N-트리클로로아세틸, N-트리플루오로아세틸, N-페닐아세틸, N-3-페닐프로피오닐, N-피콜리노일, N-3-피리딜-카복사미드, N-벤조일페닐알라닐 유도체, N-벤조일 및 N-p-페닐벤조일이 포함된다.Examples of the amide include N-formyl, N-acetyl, N-chloroacetyl, N-trichloroacetyl, N-trifluoroacetyl, N-phenylacetyl, N-3-phenylpropionyl, -3-pyridyl-carboxamide, N-benzoylphenylalanine derivatives, N-benzoyl and Np-phenylbenzoyl.

보조 분해Secondary decomposition

보조 분해 기로는 N-o-니트로페닐아세틸, N-o-니트로페녹시아세틸, N-아세토아세틸, (N'-디티오벤질옥시카보닐아미노)아세틸, N-3-(p-하이드록시페닐)프로피오닐, N-3-(p-니트로페녹시)프로피오닐, N-2-메틸-2-(o-페닐아조페녹시)프로피오닐,N-4-클로로부티릴, N-3-메틸-3-니트로부티릴, N-o-니트로신나모일, N-아세틸메티오닌 유도체, N-o-니트로벤조일, N-o-(벤조일옥시메틸)벤조일 및 4,5-디페닐-3-옥사졸린-2-온이 포함된다.Examples of the secondary decomposer include non-nitrophenylacetyl, non-nitrophenoxyacetyl, N-acetoacetyl, (N'-dithiobenzyloxycarbonylamino) acetyl, N-3- (p-hydroxyphenyl) Propyl, N-3-methyl-3- (p-nitrophenoxy) propionyl, N-2- Nitrobenzoyl, No- (benzoyloxymethyl) benzoyl, and 4,5-diphenyl-3-oxazolin-2-one.

사이클릭 이미드 유도체Cyclic imide derivative

사이클릭 이미드 유도체로는 N-프탈이미드, N-디티아숙시노일, N-2,3-디페닐-말레오일, N-2,5-디메틸피롤릴, N-1,1,4,4-테트라메틸디실릴아자사이클로펜탄 부가물, 5-치환된 1,3-디메틸-1,3,5-트리아자사이클로헥산-2-온, 5-치환된 1,3-디벤질-1,3,5-트리아자사이클로헥산-2-온 및 1-치환된 3,5-디니트로-4-피리도닐이 포함된다.Examples of the cyclic imide derivative include N-phthalimide, N-dithiacyclinoyl, N-2,3-diphenyl-maleoyl, N-2,5-dimethylpyrrolyl, N- Tetramethyldisilylazacyclopentane adduct, 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3- 3,5-triazacyclohexan-2-one and 1-substituted 3,5-dinitro-4-pyridonyl.

특별한 -NH 보호기Special -NH-protecting group

-NH를 위한 보호기로는 N-알킬 및 N-아릴 아민, 이민 유도체, 엔아민 유도체, 및 N-헤테로원자 유도체(예: N-금속, N-N, N-P, N-Si 및 N-S), N-설페닐 및 N-설포닐이 포함된다.Protecting groups for -NH include N-alkyl and N-arylamine, imine derivatives, enamine derivatives, and N-heteroatom derivatives (e.g., N-metal, NN, NP, N-Si and NS) Phenyl and N-sulfonyl.

N-알킬 및 N-아릴 아민N-alkyl and N-arylamine

N-알킬 및 N-아릴 아민으로는 N-메틸, N-알릴, N-[2-(트리메틸실릴)에톡시]-메틸, N-3-아세톡시프로필, N-(1-이소프로필-4-니트로-2-옥소-3-피롤린-3-일), 4급 암모늄 염, N-벤질, N-디(4-메톡시페닐)메틸, N-5-디벤조수베릴, N-트리페닐메틸, N-(4-메톡시페닐)디페닐메틸, N-9-페닐플루오레닐, N-2,7-디클로로-9-플루오레닐메틸렌, N-페로세닐메틸 및 N-2-피콜릴아민 N'-옥사이드가 포함된다.N-alkyl and N-arylamine include N-methyl, N-allyl, N- [2- (trimethylsilyl) ethoxy] 3-pyrrolidin-3-yl), quaternary ammonium salts, N-benzyl, N-di (4-methoxyphenyl) methyl, N- Phenylmethyl, N-2,7-dichloro-9-fluorenylmethylene, N-perrogenylmethyl and N-2- Picolylamine N'-oxide.

이민 유도체Imine derivative

이민 유도체로는 N-1,1-디메틸티오메틸렌, N-벤질릴덴, N-p-메톡시벤질리덴, N-디페닐메틸렌, N-[(2-피리딜)메시틸]메틸렌, N-(N',N'-디메틸아미노메틸렌), N-N'-이소프로필리덴, N-p-니트로벤질리덴, N-살리실리덴, N-5-클로로살리실리덴, N-(5-클로로-2-하이드록시페닐)페닐-메틸렌 및 N-사이클로헥실리덴이 포함된다.Examples of the imine derivative include N-1,1-dimethylthiomethylene, N-benzylidene, Np-methoxybenzylidene, N-diphenylmethylene, N - [(2- pyridyl) mesityl] methylene, N- N, N'-dimethylaminomethylene), N-N'-isopropylidene, Np-nitrobenzylidene, N-salicylidene, N- 5-chlorosalicylidene, N- -Hydroxyphenyl) phenyl-methylene and N-cyclohexylidene.

엔아민 유도체Enamine derivative

엔아민 유도체의 예는 N-(5,5-디메틸-3-옥소-1-사이클로헥세닐)이다.An example of an enamine derivative is N- (5,5-dimethyl-3-oxo-1-cyclohexenyl).

N-헤테로원자 유도체N-heteroatom derivatives

N-금속 유도체로는 N-보란 유도체, N-디페닐보린산 유도체, N-[페닐(펜타카보닐크로뮴- 또는 -텅스텐)]카베닐 및 N-구리 또는 N-아연 킬레이트가 포함된다. N-N 유도체의 예로는 N-니트로, N-니트로소 및 N-옥사이드를 포함한다. N-P 유도체의 예로는 N-디페닐포스피닐, N-디메틸티오포스피닐, N-디페닐티오포스피닐, N-디알킬 포스포릴, N-디벤질 포스포릴 및 N-디페닐 포스포릴이 포함된다. N-설페닐 유도체의 예로는 N-벤젠설페닐, N-o-니트로벤젠설페닐, N-2,4-디니트로벤젠설페닐, N-펜타클로로벤젠설페닐, N-2-니트로-4-메톡시-벤젠설페닐, N-트리페닐메틸설페닐 및 N-3-니트로피리딘설페닐이 포함된다. N-설포닐 유도체로는 N-p-톨루엔설포닐, N-벤젠설포닐, N-2,3,6-트리메틸-4-메톡시벤젠설포닐, N-2,4,6-트리메톡시벤젠설포닐, N-2,6-디메틸-4-메톡시-벤젠설포닐, N-펜타메틸벤젠설포닐, N-2,3,5,6-테트라메틸-4-메톡시벤젠-설포닐, N-4-메톡시벤젠설포닐, N-2,4,6-트리메틸벤젠설포닐, N-2,6-디메톡시-4-메틸벤젠설포닐, N-2,2,5,7,8,-펜타메틸크로만-6-설포닐, N-메탄설포닐-N-β-트리메틸실릴에탄설포닐, N-9-안트라센설포닐, N-4-(4',8'-디메톡시나프틸메틸)-벤젠설포닐, N-벤질설포닐, N-트리플루오로메틸설포닐 및 N-펜아실설포닐이 포함된다.N-metal derivatives include N-borane derivatives, N-diphenylboronic acid derivatives, N- [phenyl (pentacarbonylchromium- or -tungsten)] carbenyl and N-copper or N-zinc chelates. Examples of N-N derivatives include N-nitro, N-nitroso, and N-oxides. Examples of NP derivatives include N-diphenylphosphinyl, N-dimethylthiophosphinyl, N-diphenylthiophosphinyl, N-dialkylphosphoryl, N-dibenzylphosphoryl and N-diphenylphosphoryl . Examples of N-sulfenyl derivatives include N-benzenesulfenyl, N-nitrobenzenesulfenyl, N-2,4-dinitrobenzenesulfenyl, N-pentachlorobenzenesulfenyl, N-2- Methoxy-benzenesulfenyl, N-triphenylmethylsulphenyl, and N-3-nitropyridinesulphenyl. Examples of the N-sulfonyl derivative include Np-toluenesulfonyl, N-benzenesulfonyl, N-2,3,6-trimethyl-4-methoxybenzenesulfonyl, N-2,4,6-trimethoxybenzenesulfonyl N-2,6-dimethyl-4-methoxy-benzenesulfonyl, N-pentamethylbenzenesulfonyl, N-2,3,5,6-tetramethyl-4- methoxybenzenesulfonyl, N Methoxybenzenesulfonyl, N-2,4,6-trimethylbenzenesulfonyl, N-2,6-dimethoxy-4-methylbenzenesulfonyl, N- N-9-anthracenesulfonyl, N-4- (4 ', 8'-dimethoxynaphthyl (methanesulfonyl) Methyl) -benzenesulfonyl, N-benzylsulfonyl, N-trifluoromethylsulfonyl and N-phenacylsulfonyl.

마스킹 또는 보호되는 개시된 화합물은 선구약제, 즉 생체내에서 신진대사되거나 또는 달리 변형되어 상기 개시된 화합물을, 예컨대 신진대사중에 일시적으로 생성하는 화합물일 수 있다. 상기 변형은 혈액과 같은 체액과의 접촉, 산의 작용, 또는 간, 위장관 또는 기타 효소에 의해 야기되는 가수분해 또는 산화일 수 있다.The disclosed compounds that are masked or protected may be pioneering agents, i.e., compounds that are metabolized or otherwise modified in vivo to transiently produce the compounds disclosed above, e.g., during metabolic assays. The deformation may be contact with body fluids such as blood, action of acids, or hydrolysis or oxidation caused by liver, gastrointestinal tract or other enzymes.

본 발명의 특징은 하기 실시예에서 추가로 기술된다.The features of the invention are further described in the following examples.

E. 실시예E. Example

생물학적 실시예Biological example

실시예 1Example 1

스트렙토조신-유도된 정적 무해자극통증에 미치는 PD 198306의 효과Effects of PD 198306 on Streptozocin-Induced Static Harmful Stimulation Pain

동물animal

반틴 앤드 킹만(Bantin and Kingman)(영국 훌 소재)으로부터 수득한 수컷 스프라구 다울리(Sprague Dawley) 래트(250 내지 300g)를 3개의 군으로 사육하였다. 모든 동물은 자유롭게 먹이 및 물을 공급하면서 12시간 밝음/어두움 주기(07시 00분에는 밝음)하에 보관되었다. 모든 실험은 약물 치료에 대해 모르는 관찰자에 의해 수행되었다.Male Sprague Dawley rats (250-300 g) obtained from Bantin and Kingman (Hull, England) were raised in three groups. All animals were housed under a 12-hour light / dark cycle (light at 07:00) while freely feeding and watering. All experiments were performed by observers who were unaware of the medication.

래트에서의 당뇨병의 발생The incidence of diabetes in rats

래트에서, 이전에 기술된 바와 같이, 스트렙토조신의 1회 복강내 주사(50mg/kg)에 의해 당뇨병을 유발시켰다(코테익스(Courteix) 등, 1993).In rats, as previously described, diabetes was induced by a single intraperitoneal injection of streptozocin (50 mg / kg) (Courteix et al., 1993).

정적 무해자극통증의 평가Assessment of static harmless irritative pain

세메스-바인스타인 폰 프레이 헤어를 사용하여 기계적 과민반응을 측정하였다(미국 일리노이주 스토엘팅 소재). 동물을 이들의 발 아래쪽으로 접근할 수 있도록 철망 바닥 우리에 위치시킨다. 실험을 시작하기 이전에, 동물을 이러한 환경에 길들였다. 기계적 과민반응은 6초 이하 동안 힘을 증가시키면서(0.7, 1.2, 1.5, 2, 3.6, 5.5, 8.5, 11.8, 15.1 및 29g) 동물의 오른쪽 뒷발의 발바닥면에 폰 프레이 헤어를 댐으로써 시험하였다. 일단 도피 반응이 나타나면, 다음에는 폰 프레이 헤어를 감소시키면서 출발하여 반응이 일어나지 않을 때까지 발을 재시험한다. 발을 들어올릴 뿐만 아니라 반응이 유도되는 29g의 가장 큰 힘은 결국 최종점(cut-off point)을 나타내는 것이었다. 반응을 유발시키는데 필요한 가장 적은 힘을 발 도피 역치(PWT)(g)로서 기록하였다.The mechanical hypersensitivity was measured using a Sesame-Vinsutain von Frey hair (Stoerting, Illinois, USA). Place the animal on the bottom of the wire net so that it can be accessed below the feet of the animal. Prior to starting the experiment, animals were tame to this environment. Mechanical hypersensitivity was tested by damaging von Frey hair on the plantar surface of the right hind paw of the animal (0.7, 1.2, 1.5, 2, 3.6, 5.5, 8.5, 11.8, 15.1 and 29 g) Once the escape response appears, start with a decrease in the von Frey hair and retest the foot until no reaction occurs. The greatest force of 29 grams, which not only lifts the feet but also induces a reaction, is the ultimate cut-off point. The lowest force required to induce the response was recorded as the footing threshold (PWT) (g).

약물drug

PD 198306 [N-사이클로프로필메톡시-3,4,5-트리플루오로-2-(4-요오도-메틸-페닐아미노)-벤즈아미드] 및 CI-1008(프레가발린)은 파케-다비스(Parke-Davis)(미국 미시간주 앤 아보 소재)에서 합성되었다. PD198306을 크레모포르:에탄올:물 (1:1:8) 비히클 중에서 현탁시켰다. 프레가발린을 물에 용해시켰다. 화합물을 둘다 경구로 투여하였다. 스트렙토조신(영국 알드리치)을 0.9% w/v NaCl중에 용해시키고, 복강내로 투여하였다. 약물 투여는 1ml/kg의 부피로 실시되었다.PD 198306 [N-Cyclopropylmethoxy-3,4,5-trifluoro-2- (4-iodo-methyl- phenylamino) -benzamide] and CI-1008 (pregabalin) Was synthesized in Parke-Davis (Annabo, Mich., USA). PD198306 was suspended in a cremorph: ethanol: water (1: 1: 8) vehicle. The pregabalin was dissolved in water. Both compounds were administered orally. Streptozocin (UK Aldrich) was dissolved in 0.9% w / v NaCl and administered intraperitoneally. Drug administration was carried out at a volume of 1 ml / kg.

통계치Statistics

비-파라메트릭한(non-parametric) 결과를 위해 크루스칼-왈리스(Kruskall-Wallis) ANOVA를 사용하여 정적 무해자극통증 데이터를 분석한 후, 만-휘트니 t 시험에 의해 언제 유의적인지에 대해 분석하였다.After analyzing the static harmless stimulus pain data using Kruskall-Wallis ANOVA for non-parametric results, it was analyzed for significance by the Mann-Whitney t test Respectively.

실험 프로토콜Experimental Protocol

PD 198306(30mg/kg, p.o.), 비히클(크레모포르:에탄올:물, 1:1:8) 또는 프레가발린(30mg/kg, p.o.)(시험)의 경구 투여 이전(기준선, BL) 및 1시간 이후에, 정적 무해자극통증을 폰 프레이 헤어로 평가하였다. 다음날 오전 및 오후에 동물에게 동일한 화합물을 다시 투여하였다. 동물이 시험 조건에 습관화되는 것을 최소화하기 위해서, 정적 무해자극통증은 오후 투여 이전 및 1시간 이후에만 평가하였다. 반복 투여된 화합물에 대한 내성의 잠재적 증가를 방지하기 위해, 프레가발린으로 치료된 동물에게 오전 투여시 물을 공급하였다.Prior to oral administration (baseline, BL) of PD 198306 (30 mg / kg, po), vehicle (cremorph: ethanol: water, 1: 1: 8) or pregabalin (30 mg / kg, po) After one hour, static harmless stimulation pain was evaluated as von Frey hair. The same compound was administered again to the animals in the morning and afternoon the next day. To minimize the habituation of animals to the test conditions, static harmless stimulation pain was evaluated only before and 1 hour after the afternoon administration. To prevent the potential increase in tolerance to repeatedly administered compounds, animals treated with pregabalin were dosed with water during the morning dosing.

제 1 일Day 1 제 2 일Day 2 오전: PD 198306AM: PD 198306 물water 비히클Vehicle 오후: BLAfternoon: BL 오후: BLAfternoon: BL PD 198306PD 198306 PD 198306PD 198306 프레가발린Pregabalin 프레가발린Pregabalin 비히클Vehicle 비히클Vehicle 시험exam 시험exam

결과result

프레가발린(30mg/kg, p.o.)의 1회 투여는 투여 1시간 후에 스트렙토조신-유도된 정적 무해자극통증을 상당히 차단하였다. 이에 반해, PD 198306(30mg/kg,p.o.)의 1회 투여는 투여 1시간 후에 스트렙토조신-유도된 정적 무해자극통증에 전혀 효과를 나타내지 못했다(하기 참조). 그러나, 다음날 화합물을 2회 이상 투여한 후, 3번째 투여 1시간 후에는 스트렙토조신-유도된 정적 무해자극통증을 상당히 차단하였다. 이러한 효과는 다음날에 사라졌다(도 1).A single dose of pregabalin (30 mg / kg, p. O.) Significantly blocked streptozocin-induced static innocuous irritation pain after 1 hour of dosing. In contrast, a single dose of PD 198306 (30 mg / kg, p. O) did not show any effect on streptozocin-induced static innocuous irritation pain after 1 hour of administration (see below). However, after two or more doses of the compound the following day, streptozocin-induced static harmless stimulation pain was significantly blocked 1 hour after the third dose. This effect disappeared the next day (Figure 1).

실시예 2Example 2

물질 및 방법Materials and methods

동물animal

챨스 리버(Charles River)(미국 마게이트 소재)로부터 수득한 수컷 스프라구 다울리 래트(250 내지 300g)를 3 내지 6개의 군으로 사육하였다. 모든 동물은 자유롭게 먹이 및 물을 공급하면서 12시간 밝음/어두움 주기(07시 00분에는 밝음)하에 보관하였다. 모든 실험은 약물 치료에 대해 모르는 관찰자에 의해 수행되었다.Male Sprague Dawley rats (250-300 g) obtained from Charles River (Margate, USA) were bred in groups of 3 to 6. All animals were kept under a 12 hour light / dark cycle (light at 07:00) while being freely fed and watered. All experiments were performed by observers who were unaware of the medication.

래트에서, 이전에 기술된 바와 같이, 스트렙토조신의 1회 복강내 주사(50mg/kg)에 의해 당뇨병을 유도하였다(코테익스 등, 1993).In rats, diabetes was induced by intraperitoneal injection (50 mg / kg) of streptozocin, as previously described (Courtes et al., 1993).

래트에서 만성 수축 손상의 발생Generation of chronic contraction damage in rats

동물은 수술하는 동안 노즈 콘(nose cone)을 통해 2% 이소플루란 1:4 O2/NO2혼합물을 유지하여 마취시켰다. 1988년 베네트(Bennett)와 크시(Xie)에 의해 이전에 기술된 바와 같이 좌골 신경을 결찰하였다. 상기 과정 동안에 동물을 항온 블랭킷 위에 위치시켰다. 수술 준비 후, 넙다리두갈래근을 통한 무딘 절개에 의해 통상의 좌골 신경을 허벅지 중간에서 노출시켰다. 좌골 세갈래부분(trifurcation)에 근접한 약 7㎜의 신경은 조직이 부착되어 있지 않고, 4개의 봉합부분(4-0 실크)은 약 1㎜ 간격을 두고 신경 주위에서 느슨하게 묶었다. 절개 부분을 층으로 막고, 상처를 국소 항생제로 치료하였다.Animals were anesthetized by maintaining a 2% isoflurane 1: 4 O 2 / NO 2 mixture via nose cones during surgery. In 1988, Bennett and Xie ligated the sciatic nerve as previously described. During this process, the animals were placed on a thermostatic blanket. After preparation for surgery, normal sciatic nerve was exposed in the middle of the thigh by blunt dissection through the biceps femoris muscle. Approximately 7 mm of the neurons near the sciatic trifurcation were not attached to the tissue, and the four sutures (4-0 silk) were loosely bound around the nerve at intervals of about 1 mm. The incision was layered and the wound treated with topical antibiotics.

수막강내 주사Intravenous injection

래트의 등뼈를 잠시동안 이소플루란 마취제에 노출시킴으로써, PD 198306 및 프레가발린을 100㎕ 해밀톤(Hamilton) 주사기를 사용하여 10㎕의 부피로 수막강내로 투여하였다. 10㎜ 길이의 27 게이지 바늘을 사용하여 요부(lumbar region) 5와 6 사이의 수막강내 공간 사이로 주사하였다. 꼬리 떨림 반응(tail flick response)이 있다면, 침투는 성공한 것으로 판단되었다. 오토클립(autoclip)을 사용하여 상처를 밀봉하고, 래트는 주사 후 2 내지 3분 이내에 완전히 깨어난 듯 보였다.PD 198306 and pregabalin were administered intraperitoneally in a volume of 10 [mu] l using a 100 [mu] l Hamilton syringe by exposing the spine of the rat to isoflurane anesthesia for a while. A 10-mm-long 27-gauge needle was used to inject between the luminal areas 5 and 6 between the intramedullary spaces. If there was a tail flick response, penetration was considered successful. The wound was sealed using an autoclip and the rat appeared to be fully awake within 2 to 3 minutes after injection.

정적 무해자극통증의 평가Assessment of static harmless irritative pain

세메스-바인스타인 폰 프레이 헤어를 사용하여 기계적 과민반응을 측정하였다(미국 일리노이주 스토엘팅 소재). 동물을 이들의 발 아래쪽으로 접근할 수 있도록 철망 바닥 우리에 위치시킨다. 실험을 시작하기 이전에, 동물을 이러한 환경에 길들였다. 기계적 과민반응은 6초 이하 동안 힘을 증가시키면서(0.7, 1.2, 1.5, 2, 3.6, 5.5, 8.5, 11.8, 15.1 및 29g) 동물의 오른쪽 뒷발의 발바닥면에 폰 프레이 헤어를 댐으로써 시험하였다. 일단 도피 반응이 나타나면, 다음에는 폰 프레이 헤어를 감소시키면서 출발하여 반응이 일어나지 않을 때까지 발을 재시험한다. 발을 들어올릴 뿐만 아니라 반응이 유도되는 29g의 가장 큰 힘은 결국 최종점을 나타내는 것이었다. 반응을 유발시키는데 필요한 가장 적은 힘을 발 도피 역치(PWT)(g)로서 기록하였다.The mechanical hypersensitivity was measured using a Sesame-Vinsutain von Frey hair (Stoerting, Illinois, USA). Place the animal on the bottom of the wire net so that it can be accessed below the feet of the animal. Prior to starting the experiment, animals were tame to this environment. Mechanical hypersensitivity was tested by damaging von Frey hair on the plantar surface of the right hind paw of the animal (0.7, 1.2, 1.5, 2, 3.6, 5.5, 8.5, 11.8, 15.1 and 29 g) Once the escape response appears, start with a decrease in the von Frey hair and retest the foot until no reaction occurs. The largest force of 29 grams, which not only lifts the feet but also induces a reaction, ultimately represents the final point. The lowest force required to induce the response was recorded as the footing threshold (PWT) (g).

실험 프로토콜Experimental Protocol

PD 198306(1 내지 30㎍/㎏, i.t.), 비히클(크레모포르:에탄올:물, 1:1:8) 또는 프레가발린(10㎍, i.t.)의 수막강내 또는 발바닥내 투여 이전(기준선, BL), 및 투여 0.5시간, 1시간 및 2시간 이후에, 정적 무해자극통증을 폰 프레이 헤어로 평가하였다. 경구 투여 실험을 위해, PD 198306(3 내지 30㎎/㎏, p.o.), 비히클(크레모포르:에탄올:물, 1:1:8) 또는 프레가발린(30㎎/㎏, p.o.)의 경구 투여 이전(기준선, BL) 및 1시간 이후에, 정적 무해자극통증을 폰 프레이 헤어로 평가하였다. 다음날 오전 및 오후에 동물에게 동일한 화합물을 다시 투여하였다. 정적 무해자극통증은 오전 투여 이전 및 오전 투여 1시간 이후에 평가하였다. 오후에, 스트렙토조신으로 치료한 동물에 대해, 투여 이전, 투여 1시간, 2시간 및 3시간 이후의 정적 무해자극통증을 평가하였다. CCI 동물을 투여 이전, 투여 1시간 및 2시간 이후에 평가하였다.Prior to intravenous or plantar administration of PD 198306 (1 to 30 μg / kg, it), vehicle (cremophor: ethanol: water, 1: 1: 8) or pregabalin (10 μg, , &Lt; / RTI &gt; BL), and after 0.5 hours, 1 hour, and 2 hours of administration, static harmless irritative pain was evaluated as von Frey hair. For oral administration experiments, oral administration of PD 198306 (3 to 30 mg / kg, po), vehicle (cremophor: ethanol: water, 1: 1: 8) or pregabalin (30 mg / kg, po) Before (baseline, BL) and after 1 hour, static harmless stimulation pain was rated as von Frey hair. The same compound was administered again to the animals in the morning and afternoon the next day. Static innocuous irritation pain was assessed before the morning and one hour after the morning dosing. In the afternoon, animals treated with streptozocin were evaluated for static non-irritant pain prior to administration, 1 hour, 2 hours and 3 hours after administration. CCI animals were evaluated before, 1 hour and 2 hours after administration.

사용된 약물Drugs Used

PD 198306 및 프레가발린은 파케-다비스(미국 미시간주 앤 아보 소재)에서 합성되었다. PD198306을 크레모포르:에탄올:물(1:1:8) 비히클중에 현탁시켰다. 프레가발린을 물에 용해시켰다. 화합물을 둘다 각각 1㎖/㎏, 10㎕ 및 100㎕의 부피로 경구, 수막강내 또는 발바닥내로 투여하였다. 스트렙토조신(영국, 알드리치)을 0.9% w/v NaCl중에 용해시키고, 1㎖/㎏의 부피로 복강내로 투여하였다.PD 198306 and pregabalin were synthesized in Pace-Davis (Annabo, Mich., USA). PD198306 was suspended in a cremorph: ethanol: water (1: 1: 8) vehicle. The pregabalin was dissolved in water. Both compounds were administered orally, intraperitoneally or into the sole, at a volume of 1 ml / kg, 10 [mu] l and 100 [mu] l, respectively. Streptozocin (Aldrich, England) was dissolved in 0.9% w / v NaCl and administered intraperitoneally at a volume of 1 ml / kg.

통계치Statistics

비-파라메트릭한 결과를 위해 크루스칼-왈리스 ANOVA를 사용하여 데이터를 분석한 후, 만-휘트니 t 시험에 의해 언제 유의적인지에 대해 분석하였다.Data were analyzed using the Kruskal-Wallis ANOVA for non-parametric results and then analyzed for significance by the Mann-Whitney test.

결과result

1. 전신 투여 후 정적 무해자극통증에 대한 PD 198306의 효과1. Effect of PD 198306 on static harmless stimulant pain after systemic administration

1.1. 스트렙토조신-유도된 정적 무해자극통증에 대한 PD 198306의 효과1.1. Effect of PD 198306 on Streptozocin-Induced Static Harmful Stimulation Pain

프레가발린의 1회 투여(30㎎/㎏, p.o.)는, 투여 1시간 후 스트레토조신-유도된 정적 무해자극통증을 상당히 차단시켰다. 이에 반해, PD 198306의 1회 투여(3 내지 30㎎/㎏, p.o.)는 투여 1시간 후 스트렙토조신-유도된 정적 무해자극통증에 전혀 효과를 나타내지 못했다(도 2). 그러나, 다음날 화합물을 2회 이상 투여한 후, PD 198306(30㎎/㎏)은 3번째 투여 후 2시간 동안 스트렙토조신-유도된 정적 무해자극통증을 상당히 차단시켰다(도 2).One dose of pregabalin (30 mg / kg, p.o.) significantly blocked stretocosin-induced static harmless irritation pain after 1 hour of dosing. In contrast, a single dose (3-30 mg / kg, p.o.) of PD 198306 showed no effect on streptozocin-induced static innocuous irritation pain after 1 hour of dosing (FIG. 2). However, after two or more administrations of the compound the following day, PD 198306 (30 mg / kg) significantly blocked streptozocin-induced static harmless irritation pain for 2 hours after the third dose (FIG. 2).

1.2. CCI-유도된 정적 무해자극통증에 대한 PD 198306의 효과1.2. Effect of PD 198306 on CCI-induced static harmless pain

프레가발린의 1회 투여(30㎎/㎏, p.o.)는, 투여 1시간 후 스트레토조신-유도된 정적 무해자극통증을 상당히 차단시켰다. 이에 반해, PD 198306의 1회 또는 다수 투여(3 내지 30㎎/㎏, p.o.)는 모두 CCI-유도된 정적 무해자극통증에 전혀 효과를 나타내지 못했다(도 3).One dose of pregabalin (30 mg / kg, p.o.) significantly blocked stretocosin-induced static harmless irritation pain after 1 hour of dosing. In contrast, single or multiple doses of PD 198306 (3 to 30 mg / kg, p. O) did not show any effect on CCI-induced static innocuous irritation pain (FIG. 3).

2. 수막강내 투여 후 정적 무해자극통증에 대한 PD 198306의 효과2. Effect of PD 198306 on static harmless stimulation pain after intrathecal administration

3 및 10㎍의 MED로 각각 PD 198306(1 내지 30㎍) 투여량-의존적 수막강내로의 투여는, 스트렙토조신(도 4) 및 CC1(도 5)으로 유도된 동물 둘다에서 정적 무해자극통증의 유지를 차단시켰다. 이러한 항-무해자극통증 효과는 1시간 동안 지속되었다.3 and 10 μg of MED into PD 198306 (1 to 30 μg) dose-dependent aqueous humor, respectively, resulted in a significant reduction of static harmless stimulation pain in both streptozocin (FIG. 4) and CC1 Maintenance. These anti-harmless stimulant effects lasted for 1 hour.

3. 발바닥내 투여 후 정적 무해자극통증에 대한 PD 198306의 효과3. Effect of PD 198306 on static innocuous stimulant pain after sole instillation

신경병증성 동통 모델 둘다에서의 PD 198306(30㎍)의 발바닥내 투여는, 정적 무해자극통증을 상당히 차단시켰다(도 6 및 7). 이에 반해, 100배 높은 투여량(3㎎/100㎕)으로 PD 198306을 직접 발에 1회 투여하면, 스트렙토조신(도 6) 또는 CCI(도 7)으로 유도된 무해자극통증에 대해 전혀 효과를 나타내지 못했다.In-plant administration of PD 198306 (30 μg) in both neuropathic pain models significantly blocked static harmless stimulation pain (FIGS. 6 and 7). On the contrary, administration of PD 198306 with a dose of 100 times higher (3 mg / 100 μl) to the feet directly has no effect on the streptozocin (FIG. 6) or CCI (FIG. 7) I could not.

참고문헌references

메네트 지제이(Bennett GJ), 크시 와이-케이(Xie Y-K). 문헌 [인간에게서 관찰되는 바와 같은 정도의 동통 질환을 일으키는 래트에서의 말초 단일신경병증(A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man). Pain 1988, 33, 87-107].Bennett GJ, Xie Y-K. A peripheral mononeuropathy in rats causing a painful degree of disease as observed in humans (A peripheral mononeuropathy in rat producing disorders of pain sensation like that seen in man). Pain 1988, 33, 87-107].

코테익스 씨(Courteix C), 에쉘리어 메이(Eschalier A) 및 라바렌 제이(Lavarenne J). 문헌 [스트렙토조신-유도된 래트: 만성 동통 모델을 위한 거동 증거(Streptozocin-induced rats: behavioural evidence for a model of chronic pain). Pain 1993, 53, 81-8].Courteix C, Eschalier A and Lavarenne J. Streptozocin-induced rats: Streptozocin-induced rats (behavioral evidence for a model of chronic pain). Pain 1993, 53, 81-8].

실시예 3Example 3

래트의 신경병증성 동통 모델에서 기타 MEK 억제제의 효과Effect of Other MEK Inhibitors on Neuropathic Pain Model in Rats

요약summary

상이한 결합 친화도를 갖는 몇몇의 MEK 억제제의 효과는, 폰 프레이 헤어를사용하여 정적 무해자극통증을 평가함으로써, 래트의 신경병증성 통증의 CCI 모델에서 조사하였다. PD 219622 또는 PD 297447의 수막강내 투여(30㎍)는 무해자극통증에 전혀 효과는 나타내지 못했다. 이러한 효과의 결여는 화합물의 낮은 친화력 또는 가용성을 반영할 수 있다. 그러나, 높은 결합 친화력을 갖는 PD 254552 또는 PD 184352의 수막강내 투여(30㎍)는 CCI 동물에서 정적 무해자극통증의 유지를 차단하였다. 항-무해자극통증 효과는 주사 후 30분 동안만 분명하였으며, 이는 결국 프레가발린(100㎍)에서 관찰된 것보다 짧은 것이다. 이러한 효과의 크기는 PD 184352 30㎍ 및 프레가발린 100㎍과 유사하였다. 이러한 연구로부터, MEK 억제제는 수막강내로 투여한 경우 CCI-유도된 신경병증성 래트에서 항-무해자극통증 효과를 나타내고, 항-무해자극통증 효과는 화합물의 친화력과 상관관계가 있는 것으로 결론이 내려진다.The effect of some MEK inhibitors with different binding affinities was investigated in the CCI model of neuropathic pain in rats by evaluating static innocuous irritation pain using von Frey hair. Administration of water-in-the-tube (30 μg) of PD 219622 or PD 297447 did not show any effect on innocuous irritation pain. A lack of this effect may reflect the low affinity or availability of the compound. However, intraperitoneal administration (30 μg) of PD 254552 or PD 184352 with high binding affinity blocked maintenance of static harmless stimulation pain in CCI animals. The anti-harmless stimulant effect was evident only for 30 minutes after injection, which is eventually shorter than that observed in pregabalin (100 μg). The magnitude of this effect was similar to 30 μg of PD 184352 and 100 μg of pregabalin. From these studies it has been concluded that MEK inhibitors have an anti-innocuous irritative pain effect in CCI-induced neuropathic rats when administered intrathecally, and that the anti-innocuous stimulant effect is correlated with the affinity of the compound .

래트에서 만성 수축 손상을 발생시키고, 시험 화합물을 주사하고, 정적 무해자극통증을 평가하기 위한 동물 및 방법은 상기 실시예 2에 따랐다. PD 219622, PD 297447, PD 184352, PD 254552 및 프레가발린을 모든 PD 화합물에 대해 30㎍ 및 프레가발린에 대해 100㎍의 투여량으로 수막강내로 투여하였다. 정적 무해자극통증은 폰 프레이 헤어를 사용하여 화합물의 수막강내 투여 이전(기준선, BL), 및 0.5시간, 1시간 및 2시간 후에 평가하였다.Animals and methods for generating chronic contraction damage in rats, injecting test compounds and evaluating static harmless stimulation pain were according to Example 2 above. PD 219622, PD 297447, PD 184352, PD 254552, and pregabalin were administered intraperitoneally at a dose of 30 μg for all PD compounds and 100 μg for pregabalin. Static innocuous irritative pain was assessed prior to in vivo administration of compound (baseline, BL), and 0.5 h, 1 h, and 2 h after use of von Frey hair.

사용된 약물Drugs Used

PD 297447, PD 219622, PD 254552, PD184352(CI-1040) 및 프레가발린은 파케-다비스(미국 미시간주 앤 아보 소재)에서 합성하였다. PD 297447, PD219622, PD 254552 및 PD184352을 크레모포르:에탄올:물(1:1:8) 비히클중에 현탁시켰다. 프레가발린을 물에 용해시켰다. 모든 화합물을 10㎕의 부피로 수막강내로 투여하였다.PD 297447, PD 219622, PD 254552, PD184352 (CI-1040) and pregabalin were synthesized in Perke-Davis (Annabo, Michigan). PD 297447, PD219622, PD 254552 and PD184352 were suspended in cremorph: ethanol: water (1: 1: 8) vehicle. The pregabalin was dissolved in water. All compounds were administered into the aqueous humor with a volume of 10 mu l.

통계치Statistics

비-파라메트릭한 결과를 위해 크루스칼-왈리스 ANOVA를 사용하여 데이터를 분석한 후, 만-휘트니 t 시험에 의해 언제 유의적인지에 대해 분석하였다.Data were analyzed using the Kruskal-Wallis ANOVA for non-parametric results and then analyzed for significance by the Mann-Whitney test.

결과result

수막강내로 투여된 PD 297447 또는 PD 219622(30㎍)은 무해자극통증에 대해 전혀 효과를 나타내지 못했다. 이러한 효과의 결여는 화합물의 낮은 친화력(각각 965nM 및 100nM)을 반영할 수 있다. 그러나, PD 184352 또는PD 254552의 수막강내 투여(30㎍)는 CCI 동물에서 정적 무해자극통증의 유지를 차단하였다(도 8 참조). 이러한 화합물들은 높은 친화력(각각 2 및 5 nM)을 가졌다. 항-무해자극통증 효과는 주사 후 30분 동안만 분명하였으며, 이는 결국 프레가발린(100㎍)에서 관찰된 것보다 짧은 것이다. 이러한 효과의 크기는 PD 184352 30㎍ 및 프레가발린 100㎍과 유사하였다.PD 297447 or PD 219622 (30 占 퐂) administered in the menstrual fluid showed no effect on harmless stimulation pain. The lack of this effect can reflect the low affinity of the compounds (965 nM and 100 nM, respectively). However, the intrathecal administration (30 μg) of PD 184352 or PD 254552 blocked maintenance of static harmless irritative pain in CCI animals (see FIG. 8). These compounds had high affinities (2 and 5 nM, respectively). The anti-harmless stimulant effect was evident only for 30 minutes after injection, which is eventually shorter than that observed in pregabalin (100 μg). The magnitude of this effect was similar to 30 μg of PD 184352 and 100 μg of pregabalin.

상기 결과는, MEK 억제제가 수막강내로 투여한 경우 CCI-유도된 신경병증성 래트에서 항-무해자극통증 효과를 나타내고, 항-무해자극통증 효과는 화합물의 친화력과 상관관계가 있는 것을 나타낸다.These results indicate that the anti-noxious stimulation pain effect is exhibited in the CCI-induced neuropathic rats when the MEK inhibitor is administered into the aqueduct, and that the anti-harmless stimulation pain effect is correlated with the affinity of the compound.

화학적 실시예Chemical embodiment

실시예 1Example 1

[4-클로로-2-(4,4-디메틸-4,5-디하이드로-옥사졸-2-일)-페닐]-(4-요오도-2-메틸-페닐)-아민(18)(반응식 2, R1= Cl, R2= R3= H, R4= CH3) (4-chloro-2- (4,4-dimethyl-4,5-dihydro-oxazol-2-yl) -phenyl] Reaction formula 2, R 1 = Cl, R 2 = R 3 = H, R 4 = CH 3 )

a) 5-클로로-2-메톡시벤조산 16(14.8g, 0.0793몰)과 SOCl2(28.31g, 14.97㎖, 0.1584몰)의 혼합물을 2시간 동안 환류시켰으며, 제거된 과량의 SOCl2는 백색 잔류물로 남았다. 고형물을 CH2Cl2중에 용해시키고, 빙욕으로 냉각된 CH2Cl2중의 2-아미노-2-메틸-1-프로판올의 용액(13.98g, 14.97㎖, 0.1584몰)에 첨가하였다. 상기 빙욕을 제거하고, 3시간 동안 실온에서 교반시키면 백색 고형물이 침전되었다. 침전물을 여과시켜 분리하고 폐기시켰다. 여액을 농축시키면, 진한 무색 오일이 남았다. 상기 오일에 SOCl2(17.4㎖)를 적가하였다. 발열 반응이 일어나서 자유 유동성 용액이 생성되었다. 30분 동안 교반한 후, 반응 혼합물을 Et2O(200㎖)중에 부었다. 오일이 분리되었다. Et2O 층을 따라 제거하고 폐기시켰다. 유성 잔류물을 소량의 물중에 용해시키고, 수성 20% NaOH로 염기화시키고, Et2O로 추출하였다. Et2O 층을 건조시키고(K2CO3), 농축시켜 황갈색 오일로서 화합물(17)을 수득하였다. 수율 14.63g(77%).a) A mixture of 5-chloro-2-methoxybenzoic acid 16 (14.8 g, 0.0793 moles) and SOCl 2 (28.31 g, 14.97 ml, 0.1584 moles) was refluxed for 2 hours and the excess SOCl 2 removed was white It remained as a residue. The solid was dissolved in CH 2 Cl 2 and was added to a solution (13.98g, 14.97㎖, 0.1584 mol) of cooled with an ice bath CH 2 Cl 2 solution of 2-amino-2-methyl-1-propanol. The ice bath was removed and stirred at room temperature for 3 hours to precipitate a white solid. The precipitate was filtered off and discarded. The filtrate was concentrated to leave a thick, colorless oil. SOCl 2 (17.4 mL) was added dropwise to the oil. An exothermic reaction occurred and a free flowing solution was produced. After stirring for 30 min, the reaction mixture was poured into Et 2 O (200 mL). The oil was separated. The Et 2 O layer was removed and discarded. The oily residue was dissolved in a small amount of water, and basified with aqueous 20% NaOH and extracted with Et 2 O. The Et 2 O layer was dried (K 2 CO 3 ) and concentrated to give compound (17) as a tan oil. Yield 14.63 g (77%).

b) LDA(THF중의 2.0M 용액 5㎖)를 -78℃에서 THF(15㎖)중의 4-요오도-2-메틸아닐린의 용액(2.33g, 0.010몰)에 첨가하였다. 상기 혼합물을 30분 동안 -78℃에서 교반하였다. 이에 THF(15㎖)중의 화합물(17)의 용액(1.199g, 0.005몰)을 첨가하였다. 혼합물을 실온으로 가온시키면서 16시간 동안 교반하였다. 반응 혼합물을 수성 NH4Cl로 급냉시키고, Et2O로 추출하였다. Et2O 층을 건조시키고(MgSO4), 농축시켜 갈색 오일로서 조질의 화합물(18)을 수득하였다. 상기 오일을 실리카 칼럼 크로마토그래피상에서 정제시켰다. CHCl2로 용출시켜 갈색 오일로서 순수한 화합물(18) 1.7g(77%)을 수득하였다. 상기 오일 409㎎을 Et2O중에서 용해시키고, Et2O-HCl로 처리하여 밝은 황색 고형 침전물로서 HCl 염을 수득하였다. 수율 356.4㎎(81%); 융점 324 내지 330℃; C18H18N2OClI·0.5H2O에 대한 분석 계산치/측정치: C, 44.47/44.32; H, 4.15/3.94; N, 5.76/5.66.b) LDA (5 mL of a 2.0M solution in THF) was added to a solution of 4-iodo-2-methylaniline (2.33 g, 0.010 mol) in THF (15 mL) at -78 ° C. The mixture was stirred at -78 &lt; 0 &gt; C for 30 min. To this was added a solution of compound (17) (1.199 g, 0.005 mol) in THF (15 mL). The mixture was stirred for 16 hours while warming to room temperature. The reaction mixture was quenched with aqueous NH 4 Cl and extracted with Et 2 O. The Et 2 O layer was dried (MgSO 4 ) and concentrated to give crude compound (18) as a brown oil. The oil was purified on silica column chromatography. Eluted with CHCl 2 to give the pure compound (18) 1.7g (77%) as a brown oil. The oil 409㎎ to give the HCl salt was dissolved in Et 2 O and, by treatment with Et 2 O-HCl as a light yellow solid precipitate. Yield 356.4 mg (81%); Melting point 324 to 330 캜; Anal Calcd for C 18 H 18 N 2 OC 1 .5H 2 O Calcd / C: 44.47 / 44.32; H, 4.15 / 3.94; N, 5.76 / 5.66.

실시예 2Example 2

[2,3-디플루오로-6-(1H-테트라졸-5-일)-페닐]-(4-요오도-2-메틸-페닐)-아민Phenyl] - (4-iodo-2-methyl-phenyl) -amine &lt; EMI ID =

[2,3-디플루오로-6-시아노-페닐]-(4-요오도-2-메틸-페닐)-아민(1.11g, 3밀리몰), 소듐 아지드(0.255g, 3.9밀리몰) 및 트리에틸아민 하이드로클로라이드 (0.537g, 3.9밀리몰)를 모두 톨루엔 10㎖중에 현탁시키고, 12시간 동안 100℃에서 교반하였다. 혼합물을 농축시키고, 잔류물을 에틸 아세테이트/메탄올(10/1)을 사용하는 칼럼 크로마토그래피에 의해 정제시켜 포움형 고형물로서 생성물을 수득하였다. 수율(약 50%); 융점: 83.4 내지 88.7℃.Phenyl) - (4-iodo-2-methyl-phenyl) -amine (1.11 g, 3 mmol), sodium azide (0.255 g, 3.9 mmol) and Triethylamine hydrochloride (0.537 g, 3.9 mmol) was suspended in 10 ml of toluene and stirred at 100 캜 for 12 hours. The mixture was concentrated and the residue was purified by column chromatography using ethyl acetate / methanol (10/1) to give the product as a foamy solid. Yield (about 50%); Melting point: 83.4-88.7 占 폚.

실시예 3Example 3

[6-(4,4-디메틸-4,5-디하이드로-옥사졸-2-일)-2,3-디플루오로-페닐]-(4-요오도-2-메틸-페닐)-아민Phenyl] - (4-iodo-2-methyl-phenyl) -amine &lt; EMI ID =

디클로로메탄 30㎖중의 3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-벤조산(1.17g, 3밀리몰), 옥살릴 클로라이드(0.457g, 3.6밀리몰)의 용액을 디메틸포름아미드 2방울로 처리하고, 3시간 동안 실온에서 교반한 후, 농축시켰다. 잔류물을 디클로로메탄 25㎖중에 용해시킨 후, 용액을 0℃에서 디클로로메탄 25㎖중의 2-아미노-2-메틸-1-프로판올(0.623g, 7밀리몰)의 용액에 적가한 후, 12시간 동안 실온에서 교반하고, 침전물을 여거하고, 여액을 물, 5% 수성 중탄산나트륨, 1N HCl 및 염수로 세척하고, 황산나트륨으로 건조시켰다. 농축시켜 조질의 생성물을 수득한 후, 티오닐 클로라이드를 0℃에서 첨가하고, 15시간 동안 실온에서 교반한 후,농축시키고, 잔류물을 디클로로메탄 30㎖중에 용해시키고, 1N HCl을 첨가하여 pH값이 11이 되도록 조정하고, 이를 분리하고, 클로로포름으로 추출하고, 황산나트륨으로 건조시켰다. 농축시킨 후, 헥산/디클로로메탄(20/1)을 사용하는 칼럼을 통과시켜 백색 결정으로서 화합물을 수득하였다. 수율(65%); 융점: 103.7 내지 104.4℃.A solution of 3,4-difluoro-2- (4-iodo-2-methyl-phenylamino) -benzoic acid (1.17 g, 3 mmol), oxalyl chloride (0.457 g, 3.6 mmol) in 30 ml dichloromethane Was treated with 2 drops of dimethylformamide, stirred at room temperature for 3 hours and then concentrated. After dissolving the residue in 25 ml of dichloromethane, the solution was added dropwise to a solution of 2-amino-2-methyl-1-propanol (0.623 g, 7 mmol) in 25 ml of dichloromethane at 0 & After stirring at room temperature, the precipitate was filtered off and the filtrate was washed with water, 5% aqueous sodium bicarbonate, 1N HCl and brine, and dried over sodium sulfate. After concentrating to give the crude product, thionyl chloride is added at 0 &lt; 0 &gt; C and stirred at room temperature for 15 hours, then concentrated and the residue is dissolved in 30 ml of dichloromethane and 1 N HCl is added to adjust the pH value Was adjusted to 11, which was separated, extracted with chloroform, and dried over sodium sulfate. Concentrated and passed through a column using hexane / dichloromethane (20/1) to give the compound as white crystals. Yield (65%); Melting point: 103.7-104.4 占 폚.

실시예 4Example 4

3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-벤조산 메틸 에스테르Difluoro-2- (4-iodo-2-methyl-phenylamino) -benzoic acid methyl ester

3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-벤조산(5g)을 메탄올 100㎖중에 용해시키고, 농축된 황산 5방울을 첨가하고, 4일 동안 환류시켰다. 헥산/디클로로메탄을 사용하는 칼럼을 통과시켜 백색 결정으로서 화합물을 수득하였다. 수율(50%); 융점: 90.1 내지 90.4℃.4-Difluoro-2- (4-iodo-2-methyl-phenylamino) -benzoic acid (5 g) was dissolved in 100 ml methanol, 5 drops of concentrated sulfuric acid were added and refluxed for 4 days . The product was passed through a column using hexane / dichloromethane to give the compound as white crystals. Yield (50%); Melting point: 90.1 to 90.4 占 폚.

실시예 5Example 5

5-[3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-4H-[1,2,4]트리아졸-3-일아민Phenyl] -4H- [1,2,4] triazol-3-ylamine &lt; / RTI &gt;

아미노구아니딘 니트레이트(1.65g, 12밀리몰)를 0℃에서 메탄올(12㎖)중의 소듐 메톡사이드(0.648g, 12밀리몰)의 용액에 첨가한 후, 3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-벤조산을 메탄올의 용액으로서 첨가하고, 20시간 동안 환류시키고, 헥산/에틸 아세테이트를 사용하는 칼럼을 통과시켜 백색 결정으로서 화합물을 수득하였다. 수율(60%); 융점: 191.7 내지 192.0℃.Aminoguanidine nitrate (1.65 g, 12 mmol) was added to a solution of sodium methoxide (0.648 g, 12 mmol) in methanol (12 mL) at 0 ° C followed by the addition of 3,4- difluoro-2- Iodo-2-methyl-phenylamino) -benzoic acid as a solution of methanol, refluxing for 20 h and passing through a column using hexane / ethyl acetate to give the compound as white crystals. Yield (60%); Melting point: 191.7 to 192.0 占 폚.

실시예 6Example 6

5-[3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-[1,3,4]옥사디아졸-2-일아민Phenyl] - [1,3,4] oxadiazol-2-ylamine &lt; / RTI &gt;

디옥산 5㎖중의 3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-벤조산의 용액에 시아노겐브로마이드(0.212g, 2밀리몰)를 첨가한 후, 물 5㎖중의 중탄산나트륨(0.17g, 2밀리몰)을 첨가하였다. 생성된 혼합물을 실온에서 18시간 동안 교반하고, 용액을 농축시키고, 잔류물을 에틸 아세테이트/헥산을 사용하는 칼럼을 통과시켜 연한 황색 결정으로서 화합물을 수득하였다. 수율(58%); 융점: 183.7 내지 184.0℃.To a solution of 3,4-difluoro-2- (4-iodo-2-methyl-phenylamino) -benzoic acid in 5 ml dioxane was added cyanogen bromide (0.212 g, 2 mmol) Was added sodium bicarbonate (0.17 g, 2 mmol) in DMF. The resulting mixture was stirred at room temperature for 18 hours, the solution was concentrated and the residue was passed through a column using ethyl acetate / hexane to give the compound as pale yellow crystals. Yield (58%); Melting point: 183.7-184.0 占 폚.

실시예 7Example 7

2-[3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-벤조일]하이드라진카보티오아미드2- [3,4-difluoro-2- (4-iodo-2-methyl-phenylamino) -benzoyl] hydrazinecarbothioamide

디클로로메탄 40㎖중의 3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-벤조산(3.9g, 0.01몰), 옥살릴 클로라이드(1.90g, 0.015몰)의 용액을 디메틸포름아미드 2방울로 처리하고, 3시간 동안 실온에서 교반한 후, 농축시켰다. 잔류물을 테트라하이드로푸란 10㎖중에 용해시키고, 0℃에서 테트라하이드로푸란 50㎖중의 티오세미카바자이드(2.0g, 0.022몰)의 용액에 첨가하고, 14시간 동안 실온에서 교반하였다. 농축시킨 후, 헥산/에틸 아세테이트(1/1)를 사용하는 칼럼 크로마토그래피를 사용하여 황색 고형물로서 생성물 21.9g을 수득하였다. 수율(63%); 융점: 159.5 내지 160.0℃.A solution of 3,4-difluoro-2- (4-iodo-2-methyl-phenylamino) -benzoic acid (3.9 g, 0.01 mol) and oxalyl chloride (1.90 g, 0.015 mol) in 40 mL of dichloromethane Was treated with 2 drops of dimethylformamide, stirred at room temperature for 3 hours and then concentrated. The residue was dissolved in 10 ml of tetrahydrofuran and added to a solution of thiosemicarbazide (2.0 g, 0.022 mol) in 50 ml of tetrahydrofuran at 0 ° C and stirred at room temperature for 14 hours. Concentration followed by column chromatography using hexane / ethyl acetate (1/1) yielded 21.9 g of product as a yellow solid. Yield (63%); Melting point: 159.5 to 160.0 占 폚.

실시예 8Example 8

5-[3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-벤조일]-4H-[1,2,4]트리아졸-3-티올2- [4-iodo-2-methyl-phenylamino] -benzoyl] -4H- [1,2,4] triazole-3-thiol

2-[3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-벤조일]하이드라진카보티오아미드(1.386g, 3밀리몰)를 무수 메탄올 15㎖중에 용해시키고, 소듐 메톡사이드(메탄올중 25중량%) 2.5㎖를 0℃에서 한번에 첨가하였다. 생성된 혼합물을 17시간 동안 환류하에서 가열한 후 농축시켰다. 헥산/에틸 아세테이트를 사용하는 칼럼을 통과시켜 침상 백색 결정질로서 생성물을 수득하였다. 수율(40%); 융점: 196.5℃(분해).2- (4-iodo-2-methyl-phenylamino) -benzoyl] hydrazinecarbothioamide (1.386 g, 3 mmol) was dissolved in 15 mL of anhydrous methanol, sodium 2.5 mL of methoxide (25 wt% in methanol) was added at 0 &lt; 0 &gt; C at a time. The resulting mixture was heated at reflux for 17 hours and then concentrated. The product was passed through a column using hexane / ethyl acetate to give the product as needles white crystalline. Yield (40%); Melting point: 196.5 캜 (decomposition).

실시예 9Example 9

(2,3-디플루오로-6-[1,3,4]옥사디아졸-2-일-페닐)-(4-요오도-2-메틸-페닐)-아민(2,3-difluoro-6- [1,3,4] oxadiazol-2-yl-phenyl) - (4-iodo-2- methyl- phenyl)

3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-벤조산 하이드라자이드(146㎎, 0.36밀리몰)를 무수 EtOH 7㎖중에 현탁시키고, HC(OEt)32㎖를 pTsOH 약 3㎎과 함께 첨가하였다. 반응물을 3시간 동안 가열 환류시키고, 냉각시키고, 회전형 증발기상에서 농축시켰다. 반응물을 정제시켜(SiO2, 4:1 헥산/EtOAc) 황색 분말로서 (2,3-디플루오로-6-[1,3,4]옥사디아졸-2-일-페닐)-(4-요오도-2-메틸-페닐)-아민117㎎(79%)을 수득하였다. 융점: 144.4 내지 145.5℃(분해).(146 mg, 0.36 mmol) was suspended in 7 mL of dry EtOH and treated with a solution of HC (OEt) 3 &lt; 2 &gt; Was added with about 3 mg of pTsOH. The reaction was heated to reflux for 3 hours, cooled and concentrated on a rotary evaporator. The reaction was purified (SiO 2 , 4: 1 hexanes / EtOAc) to give (2,3-difluoro-6- [1,3,4] oxadiazol- Iodo-2-methyl-phenyl) -amine (79 mg). Melting point: 144.4-145.5 DEG C (decomposition).

실시예 10Example 10

5-[3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐-[1,3,4]옥사디아졸-2-티올2- [4-Iodo-2-methyl-phenylamino) -phenyl- [l, 3,4] oxadiazole-2-thiol

3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-벤조산 하이드라자이드(170㎎, 0.42밀리몰)를 무수 EtOH 7㎖중에 현탁시키고, 0℃로 냉각시켰다. 이황화탄소(74㎎, 0.97밀리몰)를 첨가한 후, 분말 KOH 24㎎(0.42밀리몰)을 첨가하였다. 반응물을 0℃에서 1시간 동안 교반하고, 실온에서 1시간 동안 교반하고, 3시간 동안 환류시켜 균질한 반응물을 수득하였다. 반응물을 실온으로 냉각시키자, 이 시점에서 ppt가 형성되었다. 물을 첨가한 후, 반응물을 EtOAc 5㎖로 희석시켰다. 1N HCl을 첨가하여 수성 층을 산성화시켰다(pH = 2). 상기 수성층을 EtOAc로 3회 추출하였다. 합쳐진 유기 층을 Na2SO4상에서 건조시키고, 농축시켜 황색 분말로서 5-[3,4-디플루오로-2-(4-요오도-2-메틸-페닐)-[1,3,4]옥사디아졸-2-티올96㎎(51%)을 수득하였다. 융점: 231.8 내지 232.8℃(분해).1H NMR(400MHz, CDCl3) δ 7.62 (m, 2H), 7.47 (s, 1H), 7.30(복합 m, 2H), 6.44 (dd, J = 8.0, 4.5 Hz, 1H), 2.19 (s, 3H).(4-Iodo-2-methyl-phenylamino) -benzoic acid hydrazide (170 mg, 0.42 mmol) was suspended in 7 mL of dry EtOH and cooled to 0 <0> C. After addition of carbon disulfide (74 mg, 0.97 mmol), 24 mg (0.42 mmol) of powdered KOH were added. The reaction was stirred at 0 &lt; 0 &gt; C for 1 hour, at room temperature for 1 hour and at reflux for 3 hours to give a homogeneous reaction. When the reaction was cooled to room temperature, ppt was formed at this point. After addition of water, the reaction was diluted with 5 mL of EtOAc. 1N HCl was added to acidify the aqueous layer (pH = 2). The aqueous layer was extracted three times with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated to give 5- [3,4-difluoro-2- (4-iodo-2-methyl- phenyl) - [1,3,4] oxadiazole -2-thiol (51%). Melting point: 231.8-232.8 캜 (decomposition). 1 H NMR (400MHz, CDCl 3 ) δ 7.62 (m, 2H), 7.47 (s, 1H), 7.30 ( complex m, 2H), 6.44 (dd , J = 8.0, 4.5 Hz, 1H), 2.19 (s, 3H).

F. 기타 실시태양F. Other Embodiments

상기 개시내용 및 실시예로부터 및 하기 청구의 범위로부터, 본 발명의 본질적인 특징은 용이하게 자명하다. 또한, 본 발명의 범주는 숙련자의 지식내의 다양한 변형 및 응용을 포함한다. 실시예는 보호기의 첨가 또는 제거에 의해 변형된 개시된 화합물, 또는 개시된 화합물의 에스테르, 약학적으로 허용가능한 염, 수화물, 산 또는 아미드를 포함한다. 본 발명에 인용된 공개문헌은 그 전체가 본원에 참고로 인용되어 있다.From the foregoing disclosure and examples, and from the following claims, the essential features of the present invention are readily apparent. Further, the scope of the present invention includes various modifications and applications within the knowledge of the skilled person. Examples include the disclosed compounds modified by addition or removal of a protecting group, or esters, pharmaceutically acceptable salts, hydrates, acids or amides of the disclosed compounds. The disclosure documents cited herein are incorporated herein by reference in their entirety.

Claims (33)

하기 화학식 I의 화합물로부터 선택된 MEK 억제제, 또는 그의 약학적으로 허용가능한 염 또는 C1-8에스테르를 포함하는 조성물을 만성 동통의 치료가 필요한 환자에게 투여함을 포함하는 만성 동통의 치료방법:A method of treating chronic pain comprising administering to a patient in need of such treatment a composition comprising a MEK inhibitor, or a pharmaceutically acceptable salt or C 1-8 ester thereof, selected from a compound of formula I: 화학식 IFormula I 상기 식에서,In this formula, W는 식W represents the formula 중 하나이고,/ RTI &gt; X1은 O, S 또는 NRF이고, X2는 OH, SH 또는 NHRE이되, 여기서 RE및 RF는 각각 H 또는 C1-4알킬이고,X 1 is O, S or NR F and X 2 is OH, SH or NHR E , wherein R E and R F are each H or C 1-4 alkyl, R1및 R2는 각각 H, F, NO2, Br 및 Cl로부터 독립적으로 선택되고, R1은 또한 SO2NRGRH일 수 있거나, 또는 R1및 R2는 이들이 결합된 벤젠 고리와 함께 인돌, 이소인돌, 벤조푸란, 벤조티오펜, 인다졸, 벤즈이미다졸 또는 벤즈티오아졸을 구성하고,R 1 and R 2 are each independently selected from H, F, NO 2 , Br and Cl, and R 1 may also be SO 2 NR G R H , or R 1 and R 2 may be a benzene ring, Together form indole, isoindole, benzofuran, benzothiophene, indazole, benzimidazole or benzthioazole, R3은 H 또는 F이고,R &lt; 3 &gt; is H or F, RG, RH및 R4는 각각 H, Cl 및 CH3으로부터 독립적으로 선택되고,R G , R H and R 4 are each independently selected from H, Cl and CH 3 , R5는 H 또는 C3-4알킬이되, 여기서R 5 is H or C 3-4 alkyl, wherein 상기 탄화수소 라디칼은 각각 할로, 하이드록실, 아미노, (아미노)설포닐 및 NO2로부터 독립적으로 선택된 1 내지 3개의 치환기로 선택적으로 치환되고,Wherein said hydrocarbon radicals are each optionally substituted with 1 to 3 substituents independently selected from halo, hydroxyl, amino, (amino) sulfonyl and NO 2 , 상기 헤테로사이클릭 라디칼은 각각 할로, C3-4알킬, C3-6사이클로알킬, C3-4알케닐, C3-4알키닐, 페닐, 하이드록실, 아미노, (아미노)설포닐 및 NO2로부터 독립적으로 선택된 1 내지 3개의 치환기로 선택적으로 치환되며, 여기서 상기 치환기 알킬, 사이클로알킬, 알케닐, 알키닐 또는 페닐은 각각 또다시 할로, C1-2알킬, 하이드록실, 아미노 및 NO2로부터 독립적으로 선택된 1 또는 2개의 치환기로 선택적으로 치환된다.Wherein said heterocyclic radical is selected from the group consisting of halo, C 3-4 alkyl, C 3-6 cycloalkyl, C 3-4 alkenyl, C 3-4 alkynyl, phenyl, hydroxyl, amino, (amino) 2 independently are optionally substituted by 1 to 3 substituents selected, where the substituents alkyl, cycloalkyl, alkenyl, alkynyl or phenyl is again halo, C 1-2 alkyl, hydroxyl, amino, and NO 2 from each Lt; RTI ID = 0.0 &gt; 1 &lt; / RTI &gt; 제 1 항에 있어서,The method according to claim 1, 상기 만성 동통이 신경병증성 동통, 특발성 동통, 및 만성 알콜중독증, 비타민 결핍증, 요독증(uremia) 또는 갑상선기능저하증(hypothyroidism)과 관련된 동통으로부터 선택되는 방법.Wherein the chronic pain is selected from neuropathic pain, idiopathic pain, and pain associated with chronic alcohol intoxication, vitamin deficiency, uremia, or hypothyroidism. 제 2 항에 있어서,3. The method of claim 2, 상기 만성 동통이 신경병증성 동통 유형인 방법.Wherein said chronic pain is a neuropathic pain type. 제 3 항에 있어서,The method of claim 3, 상기 신경병증성 동통이 염증, 수술후 동통, 환지통(phantom limb pain), 작열 동통, 통풍, 삼차신경통(trigeminal neuralgia), 급성 포진 및 포진후 동통, 작열통, 당뇨병성 신경병증, 플렉서스 어벌젼(plexus avulsion), 신경종, 혈관염, 바이러스 감염, 압궤 손상, 수축 손상, 조직 손상, 사지 절단, 수술후 동통, 관절통, 및 말초 신경계와 중추 신경계 사이의 기타 다른 신경 손상중 하나와 관련된 방법.The neuropathic pain may be selected from the group consisting of inflammation, postoperative pain, phantom limb pain, burning pain, gout, trigeminal neuralgia, acute herpes and postherpetic pain, burning pain, diabetic neuropathy, avulsion, neuroma, vasculitis, viral infection, crush injury, contraction injury, tissue damage, limb amputation, postoperative pain, arthralgia, and other nerve damage between the central nervous system and the central nervous system. 제 2 항에 있어서,3. The method of claim 2, 상기 만성 동통이 만성 알콜중독증, 비타민 결핍증, 요독증 또는 갑상선기능저하증과 관련된 방법.Wherein said chronic pain is associated with chronic alcohol intoxication, vitamin deficiency, uremia or hypothyroidism. 제 2 항에 있어서,3. The method of claim 2, 상기 만성 동통이 특발성 동통과 관련된 방법.Wherein said chronic pain is associated with idiopathic pain. 제 1 항에 있어서,The method according to claim 1, 상기 만성 동통이 염증과 관련된 방법.Wherein said chronic pain is associated with inflammation. 제 1 항에 있어서,The method according to claim 1, 상기 만성 동통이 관절염과 관련된 방법.Wherein said chronic pain is associated with arthritis. 제 1 항에 있어서,The method according to claim 1, 상기 만성 동통이 수술후 동통과 관련된 방법.Wherein said chronic pain is associated with postoperative pain. 제 1 항에 있어서,The method according to claim 1, R1이 브로모 또는 클로로인 방법.Wherein R &lt; 1 &gt; is bromo or chloro. 제 1 항에 있어서,The method according to claim 1, R2가 플루오로인 방법.And R &lt; 2 &gt; is fluoro. 제 1 항에 있어서,The method according to claim 1, R3이 H인 방법.Wherein R &lt; 3 &gt; 제 12 항에 있어서,13. The method of claim 12, R2및 R3이 각각 H인 방법.R 2 and R 3 are each H. 제 1 항에 있어서,The method according to claim 1, R2및 R3이 각각 플루오로인 방법.R &lt; 2 &gt; and R &lt; 3 &gt; are each fluoro. 제 14 항에 있어서,15. The method of claim 14, R1이 브로모인 방법.Wherein R &lt; 1 &gt; is bromo. 제 14 항에 있어서,15. The method of claim 14, R1이 플루오로인 방법.Wherein R &lt; 1 &gt; is fluoro. 제 1 항에 있어서,The method according to claim 1, R2가 니트로인 방법.Wherein R &lt; 2 &gt; is nitro. 제 16 항에 있어서,17. The method of claim 16, R3이 H인 방법.Wherein R &lt; 3 &gt; 제 1 항에 있어서,The method according to claim 1, R4가 클로로인 방법.Wherein R &lt; 4 &gt; is chloro. 제 1 항에 있어서,The method according to claim 1, R4가 메틸인 방법.And R &lt; 4 &gt; is methyl. 제 1 항에 있어서,The method according to claim 1, R5가 H인 방법.Wherein R &lt; 5 &gt; is H. 제 1 항에 있어서,The method according to claim 1, R5가 CH3인 방법.The method of R 5 is CH 3. 제 1 항에 있어서,The method according to claim 1, X1이 O 또는 S인 방법.Wherein X &lt; 1 &gt; is O or S; 제 1 항에 있어서,The method according to claim 1, X1이 NH 또는 NCH3인 방법.Method of X 1 is NH or NCH 3. 제 1 항에 있어서,The method according to claim 1, X2가 OH, SH 또는 NH2인 방법.X 2 is OH, SH or NH 2 . 제 1 항에 있어서,The method according to claim 1, X2가 NHCH3또는 OH인 방법.Method of X 2 is NHCH 3 or OH. 제 1 항에 있어서,The method according to claim 1, 상기 MEK 억제제가Wherein the MEK inhibitor is [5-플루오로-2-(1H-테트라졸-5-일)-페닐]-(4-요오도-2-메틸-페닐)-아민;[5-fluoro-2- (lH-tetrazol-5-yl) -phenyl] - (4-iodo-2-methyl-phenyl) -amine; [2,3-디플루오로-6-(1H-테트라졸-5-일)-페닐]-(4-요오도-2-메틸-페닐)-아민;[2,3-difluoro-6- (lH-tetrazol-5-yl) -phenyl] - (4-iodo-2-methyl-phenyl) -amine; (4-요오도-2-메틸-페닐)-[2,3,4-트리플루오로-6-(1H-테트라졸-5-일)-페닐]-아민;(4-iodo-2-methyl-phenyl) - [2,3,4-trifluoro-6- (lH-tetrazol-5-yl) -phenyl] -amine; [4-브로모-2,3-디플루오로-6-(1H-테트라졸-5-일)-페닐]-(4-요오도-2-메틸-페닐)-아민;[4-Bromo-2,3-difluoro-6- (lH-tetrazol-5-yl) -phenyl] - (4-iodo-2-methyl-phenyl) -amine; [5-플루오로-4-니트로-2-(1H-테트라졸-5-일)-페닐]-(4-요오도-2-메틸-페닐)-아민;[5-Fluoro-4-nitro-2- (lH-tetrazol-5-yl) -phenyl] - (4-iodo-2-methyl-phenyl) -amine; [2-(4,4-디메틸-4,5-디하이드로-옥사졸-2-일)-5-플루오로-페닐]-(4-요오도-2-메틸-페닐)-아민;[2- (4,4-Dimethyl-4,5-dihydro-oxazol-2-yl) -5-fluoro-phenyl] - (4-iodo-2-methyl-phenyl) -amine; [6-(4,4-디메틸-4,5-디하이드로-옥사졸-2-일)-2,3-디플루오로-페닐]-(4-요오도-2-메틸-페닐)-아민;Phenyl] - (4-iodo-2-methyl-phenyl) -amine &lt; EMI ID = ; [6-(4,4-디메틸-4,5-디하이드로-옥사졸-2-일)-2,3,4-트리플루오로-페닐]-(4-요오도-2-메틸-페닐)-아민;Phenyl) - (4-iodo-2-methyl-phenyl) - &lt; / RTI & - amine; [4-브로모-6-(4,4-디메틸-4,5-디하이드로-옥사졸-2-일)-2,3-디플루오로-페닐]-(4-요오도-2-메틸-페닐)-아민;(4-bromo-6- (4,4-dimethyl-4,5-dihydro-oxazol-2-yl) -2,3- -Phenyl) -amine &lt; / RTI &gt; [2-(4,4-디메틸-4,5-디하이드로-옥사졸-2-일)-5-플루오로-4-니트로-페닐]-(4-요오도-2-메틸-페닐)-아민;4-Nitro-phenyl] - (4-iodo-2-methyl-phenyl) - Amine; 5-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-[1,3,4]티아디아졸-2-올;5- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] - [1,3,4] thiadiazol-2-ol; 5-[3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-[1,3,4]티아디아졸-2-올;5- [3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] - [1,3,4] thiadiazol-2-ol; 5-[3,4,5-트리플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-[1,3,4]티아디아졸-2-올;5- [3,4,5-Trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] - [1,3,4] thiadiazol-2-ol; 5-[5-브로모-3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-[1,3,4]티아디아졸-2-올;5- [5-Bromo-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] - [1,3,4] thiadiazol-2-ol; 5-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-5-니트로-페닐]-[1,3,4]티아디아졸-2-올;5- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl] - [1,3,4] thiadiazol-2-ol; 5-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-[1,3,4]옥사디아졸-2-올;5- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] - [1,3,4] oxadiazol-2-ol; 5-[3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-[1,3,4]옥사디아졸-2-올;5- [3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] - [1,3,4] oxadiazol-2-ol; 5-[3,4,5-트리플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-[1,3,4]옥사디아졸-2-올;5- [3,4,5-Trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] - [1,3,4] oxadiazol-2-ol; 5-[5-브로모-3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-[1,3,4]옥사디아졸-2-올;5- [5-Bromo-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] - [1,3,4] oxadiazol-2-ol; 5-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-5-니트로-페닐]-[1,3,4]옥사디아졸-2-올;5- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl] - [1,3,4] oxadiazol-2-ol; 5-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-4H-[1,2,4]트리아졸-3-올;5- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -4H- [1,2,4] triazol-3-ol; 5-[3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-4H-[1,2,4]트리아졸-3-올;5- [3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -4H- [1,2,4] triazol-3-ol; 5-[3,4,5-트리플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-4H-[1,2,4]트리아졸-3-올;5- [3,4,5-Trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -4H- [1,2,4] triazol-3-ol; 5-[5-브로모-3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-4H-[1,2,4]트리아졸-3-올; 및2-methyl-phenylamino) -phenyl] -4H- [1,2,4] triazol-3-ol ; And 5-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-5-니트로-페닐]-4H-[1,2,4]트리아졸-3-올로부터 선택된 구조를 갖는 방법.The structure selected from 5- [4-fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl] -4H- [1,2,4] triazol- / RTI &gt; 제 1 항에 있어서,The method according to claim 1, 상기 MEK 억제제가Wherein the MEK inhibitor is 5-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-[1,3,4]티아디아졸-2-일아민;5- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] - [1,3,4] thiadiazol-2-ylamine; 5-[3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-[1,3,4]티아디아졸-2-일아민;5- [3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] - [1,3,4] thiadiazol-2-ylamine; 5-[3,4,5-트리플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-[1,3,4]티아디아졸-2-일아민;5- [3,4,5-Trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] - [1,3,4] thiadiazol-2-ylamine; 5-[5-브로모-3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-[1,3,4]티아디아졸-2-일아민;Methyl-phenylamino) -phenyl] - [1,3,4] thiadiazol-2-ylamine &lt; / RTI &gt;; 5-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-5-니트로-페닐]-[1,3,4]티아디아졸-2-일아민;5- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl] - [1,3,4] thiadiazol-2-ylamine; 5-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-[1,3,4]옥사디아졸-2-일아민;5- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] - [1,3,4] oxadiazol-2-ylamine; 5-[3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-[1,3,4]옥사디아졸-2-일아민;5- [3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] - [1,3,4] oxadiazol-2-ylamine; 5-[3,4,5-트리플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-[1,3,4]옥사디아졸-2-일아민;5- [3,4,5-Trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] - [1,3,4] oxadiazol-2-ylamine; 5-[5-브로모-3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-[1,3,4]옥사디아졸-2-일아민;Phenyl] - [1,3,4] oxadiazol-2-ylamine &lt; / RTI &gt;; 5-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-5-니트로-페닐]-[1,3,4]옥사디아졸-2-일아민;5- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl] - [1,3,4] oxadiazol-2-ylamine; 5-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-4H-[1,2,4]트리아졸-3-일아민;5- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -4H- [l, 2,4] triazol-3-ylamine; 5-[3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-4H-[1,2,4]트리아졸-3-일아민;5- [3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -4H- [1,2,4] triazol-3-ylamine; 5-[3,4,5-트리플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-4H-[1,2,4]트리아졸-3-일아민;5- [3,4,5-Trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -4H- [l, 2,4] triazol-3-ylamine; 5-[5-브로모-3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-4H-[1,2,4]트리아졸-3-일아민;Phenyl] -4H- [l, 2,4] triazol-3-yl-lH-pyrrolo [ Amine; 5-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-5-니트로-페닐]-4H-[1,2,4]트리아졸-3-일아민;5- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl] -4H- [1,2,4] triazol-3-ylamine; 5-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-[1,3,4]티아디아졸-2-티올;5- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] - [1,3,4] thiadiazole-2-thiol; 5-[3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-[1,3,4]티아디아졸-2-티올;5- [3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] - [1,3,4] thiadiazole-2-thiol; 5-[3,4,5-트리플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-[1,3,4]티아디아졸-2-티올;5- [3,4,5-Trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] - [1,3,4] thiadiazole-2-thiol; 5-[5-브로모-3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-[1,3,4]티아디아졸-2-티올;5- [5-Bromo-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] - [1,3,4] thiadiazole-2-thiol; 5-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-5-니트로-페닐]-[1,3,4]티아디아졸-2-티올;5- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl] - [1,3,4] thiadiazole-2-thiol; 5-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-[1,3,4]옥사디아졸-2-티올;5- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] - [1,3,4] oxadiazole-2-thiol; 5-[3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-[1,3,4]옥사디아졸-2-티올;5- [3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] - [1,3,4] oxadiazole-2-thiol; 5-[3,4,5-트리플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-[1,3,4]옥사디아졸-2-티올;5- [3,4,5-Trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] - [1,3,4] oxadiazole-2-thiol; 5-[5-브로모-3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-[1,3,4]옥사디아졸-2-티올;5- [5-Bromo-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] - [1,3,4] oxadiazole-2-thiol; 5-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-5-니트로-페닐]-[1,3,4]옥사디아졸-2-티올;5- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl] - [1,3,4] oxadiazole-2-thiol; 5-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-4H-[1,2,4]트리아졸-3-티올;5- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -4H- [1,2,4] triazole-3-thiol; 5-[3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-4H-[1,2,4]트리아졸-3-티올;5- [3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -4H- [1,2,4] triazole-3-thiol; 5-[3,4,5-트리플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-4H-[1,2,4]트리아졸-3-티올;5- [3,4,5-Trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -4H- [1,2,4] triazole-3-thiol; 5-[5-브로모-3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-4H-[1,2,4]트리아졸-3-티올; 및Methyl-phenylamino) -phenyl] -4H- [1,2,4] triazole-3-thiol &lt; / RTI &gt;; And 5-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-5-니트로-페닐]-4H-[1,2,4]트리아졸-3-티올로부터 선택된 구조를 갖는 방법.The structure selected from 5- [4-fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl] -4H- [1,2,4] triazole- / RTI &gt; 제 1 항에 있어서,The method according to claim 1, 상기 MEK 억제제가Wherein the MEK inhibitor is 5-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-이소티아졸-3-올;5- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -isothiazol-3-ol; 5-[3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-이소티아졸-3-올;5- [3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -isothiazol-3-ol; 5-[3,4,5-트리플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-이소티아졸-3-올;5- [3,4,5-Trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -isothiazol-3-ol; 5-[5-브로모-3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-이소티아졸-3-올;5- [5-Bromo-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -isothiazol-3-ol; 5-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-5-니트로-페닐]-이소티아졸-3-올;5- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl] -isothiazol-3-ol; 5-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-이속사졸-3-올;5- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -isoxazol-3-ol; 5-[3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-이속사졸-3-올;5- [3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -isoxazol-3-ol; 5-[3,4,5-트리플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-이속사졸-3-올;5- [3,4,5-Trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -isoxazol-3-ol; 5-[5-브로모-3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-이속사졸-3-올;5- [5-Bromo-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -isoxazol-3-ol; 5-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-5-니트로-페닐]-이속사졸-3-올;5- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl] -isoxazol-3-ol; 5-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-1H-피라졸-3-올;5- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -lH-pyrazol-3-ol; 5-[3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-1H-피라졸-3-올;5- [3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -lH-pyrazol-3-ol; 5-[3,4,5-트리플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-1H-피라졸-3-올;5- [3,4,5-Trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -lH-pyrazol-3-ol; 5-[5-브로모-3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-1H-피라졸-3-올;5- [5-Bromo-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -lH-pyrazol-3-ol; 5-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-5-니트로-페닐]-1H-피라졸-3-올;5- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl] -1H-pyrazol-3-ol; 4-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-이소티아졸-3-올;4- [4-fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -isothiazol-3-ol; 4-[3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-이소티아졸-3-올;4- [3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -isothiazol-3-ol; 4-[3,4,5-트리플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-이소티아졸-3-올;4- [3,4,5-Trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -isothiazol-3-ol; 4-[5-브로모-3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-이소티아졸-3-올;4- [5-Bromo-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -isothiazol-3-ol; 4-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-5-니트로-페닐]-이소티아졸-3-올;4- [4-fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl] -isothiazol-3-ol; 4-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-이속사졸-3-올;4- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -isoxazol-3-ol; 4-[3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-이속사졸-3-올;4- [3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -isoxazol-3-ol; 4-[3,4,5-트리플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-이속사졸-3-올;4- [3,4,5-Trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -isoxazol-3-ol; 4-[5-브로모-3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-이속사졸-3-올;4- [5-Bromo-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -isoxazol-3-ol; 4-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-5-니트로-페닐]-이속사졸-3-올;4- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl] -isoxazol-3-ol; 4-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-1-메틸-1H-피라졸-3-올;4- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -l-methyl-lH-pyrazol-3-ol; 4-[3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-1-메틸-1H-피라졸-3-올;4- [3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -1-methyl-1H-pyrazol-3-ol; 1-메틸-4-[3,4,5-트리플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-1H-피라졸-3-올;L-Methyl-4- [3,4,5-trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -lH-pyrazol-3-ol; 4-[5-브로모-3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-1-메틸-1H-피라졸-3-올; 및4- [5-Bromo-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -1-methyl-1H-pyrazol-3-ol; And 4-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-5-니트로-페닐]-1-메틸-1H-피라졸-3-올로부터 선택된 구조를 갖는 방법.2-methyl-phenylamino] -5-nitro-phenyl] -1-methyl-1H-pyrazol-3-ol. 제 1 항에 있어서,The method according to claim 1, 상기 MEK 억제제가Wherein the MEK inhibitor is 5-[2-(2-아미노-4-요오도-페닐아미노)-4-플루오로-페닐]-1-메틸-1H-[1,2,3]트리아졸-4-올;5- [2- (2-Amino-4-iodo-phenylamino) -4-fluoro-phenyl] -1-methyl-1H- [1,2,3] triazol-4-ol; 5-[2-(2-아미노-4-요오도-페닐아미노)-3,4-디플루오로-페닐]-1-메틸-1H-[1,2,3]트리아졸-4-올;5- [2- (2-Amino-4-iodo-phenylamino) -3,4-difluoro-phenyl] -1-methyl-1H- [1,2,3] triazol-4-ol; 5-[2-(2-아미노-4-요오도-페닐아미노)-3,4,5-트리플루오로-페닐]-1-메틸-1H-[1,2,3]트리아졸-4-올;Phenyl] -1-methyl-1H- [1,2,3] triazol-4- Come; 5-[2-(2-아미노-4-요오도-페닐아미노)-5-브로모-3,4-디플루오로-페닐]-1-메틸-1H-[1,2,3]트리아졸-4-올;5-Bromo-3,4-difluoro-phenyl] -1-methyl-1H- [1,2,3] triazole 4-ol; 5-[2-(2-아미노-4-요오도-페닐아미노)-4-플루오로-5-니트로-페닐]-1-메틸-1H-[1,2,3]트리아졸-4-올;5-Nitro-phenyl] -1-methyl-1H- [1,2,3] triazol-4-ol ; 5-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-3-메틸-3H-[1,2,3]트리아졸-4-올;5- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -3-methyl-3H- [1,2,3] triazol-4- 5-[3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-3-메틸-3H-[1,2,3]트리아졸-4-올;5- [3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -3-methyl-3H- [1,2,3] triazol-4-ol; 3-메틸-5-[3,4,5-트리플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-3H-[1,2,3]트리아졸-4-올;Methyl-5- [3,4,5-trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -3H- [1,2,3] triazol- Come; 5-[5-브로모-3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-3-메틸-3H-[1,2,3]트리아졸-4-올;Phenyl] -3-methyl-3H- [1,2,3] triazole &lt; / RTI &gt;4-ol; 5-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-5-니트로-페닐]-3-메틸-3H-[1,2,3]트리아졸-4-올;Phenyl] -3-methyl-3H- [1,2,3] triazol-4-ol &lt; / RTI &gt;; 4-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-2-메틸-2H-피라졸-3-올;4- [4-fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -2-methyl-2H-pyrazol-3-ol; 4-[3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-2-메틸-2H-피라졸-3-올;4- [3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -2-methyl-2H-pyrazol-3-ol; 2-메틸-4-[3,4,5-트리플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-2H-피라졸-3-올;2-Methyl-4- [3,4,5-trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -2H-pyrazol-3-ol; 4-[5-브로모-3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-2-메틸-2H-피라졸-3-올;4- [5-Bromo-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -2-methyl-2H-pyrazol-3-ol; 4-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-5-니트로-페닐]-2-메틸-2H-피라졸-3-올;4- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl] -2-methyl-2H-pyrazol-3-ol; 1-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-4-메틸-1,4-디하이드로-테트라졸-5-온;1- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -4-methyl-1,4-dihydro-tetrazol-5-one; 1-[3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-4-메틸-1,4-디하이드로-테트라졸-5-온;L- [3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -4-methyl-l, 4-dihydro-tetrazol-5-one; 1-메틸-4-[3,4,5-트리플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-1,4-디하이드로-테트라졸-5-온;L-Methyl-4- [3,4,5-trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -1,4-dihydro-tetrazol-5-one; 1-[5-브로모-3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-4-메틸-1,4-디하이드로-테트라졸-5-온;Methyl-phenylamino) -phenyl] -4-methyl-l, 4-dihydro-tetrazole-5 -On; 1-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-5-니트로-페닐]-4-메틸-1,4-디하이드로-테트라졸-5-온;1- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl] -4-methyl-1,4-dihydro-tetrazol-5-one; 1-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-1H-[1,2,3]트리아졸-4-올;L- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -lH- [l, 2,3] triazol-4- 1-[3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-1H-[1,2,3]트리아졸-4-올;L- [3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -1H- [1,2,3] triazol-4-ol; 1-[3,4,5-트리플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-1H-[1,2,3]트리아졸-4-올;L- [3,4,5-Trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -lH- [l, 2,3] triazol-4- 1-[5-브로모-3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-1H-[1,2,3]트리아졸-4-올; 및Phenyl] -lH- [l, 2,3] triazol-4-ol &lt; / RTI &gt;; And 1-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-5-니트로-페닐]-1H-[1,2,3]트리아졸-4-올로부터 선택된 구조를 갖는 방법.The structure selected from 1- [4-fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl] -1H- [1,2,3] triazol- / RTI &gt; 제 1 항에 있어서,The method according to claim 1, 상기 MEK 억제제가Wherein the MEK inhibitor is 3-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-2H-이속사졸-5-온;3- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -2H-isoxazol-5-one; 3-[3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-2H-이속사졸-5-온;3- [3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -2H-isoxazol-5-one; 3-[3,4,5-트리플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-2H-이속사졸-5-온;3- [3,4,5-Trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -2H-isoxazol-5-one; 3-[5-브로모-3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-2H-이속사졸-5-온;3- [5-Bromo-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -2H-isoxazol-5-one; 3-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-5-니트로-페닐]-2H-이속사졸-5-온;3- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl] -2H-isoxazol-5-one; [5-플루오로-2-(2-옥소-2,3-디하이드로-2I＞4_-[1,2,3,5]옥사티아디아졸-4-일)-페닐]-(4-요오도-2-메틸-페닐)-아민;4-yl) - phenyl] - (4-iodo-4-methylpiperazin-1- Methyl-phenyl) -amine &lt; / RTI &gt; [2,3-디플루오로-6-(2-옥소-2,3-디하이드로-2I＞4_-[1,2,3,5]옥사티아디아졸-4-일)-페닐]-(4-요오도-2-메틸-페닐)-아민;[2,3-difluoro-6- (2-oxo-2,3-dihydro-2I> 4 _- [1,2,3,5] oxathiadiazol- 4-iodo-2-methyl-phenyl) -amine; (4-요오도-2-메틸-페닐)-[2,3,4-트리플루오로-6-(2-옥소-2,3-디하이드로-2I＞4_-[1,2,3,5]옥사티아디아졸-4-일)-페닐]-아민;Methyl-phenyl) - [2,3,4-trifluoro-6- (2-oxo-2,3-dihydro- ] Oxathiadiazol-4-yl) -phenyl] -amine; [4-브로모-2,3-디플루오로-6-(2-옥소-2,3-디하이드로-2I＞4_-[1,2,3,5]옥사티아디아졸-4-일)-페닐]-(4-요오도-2-메틸-페닐)-아민;4-Bromo-2,3-difluoro-6- (2-oxo-2,3-dihydro- -Phenyl] - (4-iodo-2-methyl-phenyl) -amine; [5-플루오로-4-니트로-2-(2-옥소-2,3-디하이드로-2I＞4_-[1,2,3,5]옥사티아디아졸-4-일)-페닐]-(4-요오도-2-메틸-페닐)-아민;[5-fluoro-4-nitro-2- (2-oxo-2,3-dihydro-2I.4_- [1,2,3,5] oxathiadiazol- (4-iodo-2-methyl-phenyl) -amine; 4-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-4H-이속사졸-5-온;4- [4-Fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -4H-isoxazol-5-one; 4-[3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-4H-이속사졸-5-온;4- [3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -4H-isoxazol-5-one; 4-[3,4,5-트리플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-4H-이속사졸-5-온;4- [3,4,5-Trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -4H-isoxazol-5-one; 4-[5-브로모-3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-4H-이속사졸-5-온; 및4- [5-Bromo-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -4H-isoxazol-5-one; And 4-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-5-니트로-페닐]-4H-이속사졸-5-온으로부터 선택된 구조를 갖는 방법.4-fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl] -4H-isoxazol-5-one. 제 1 항에 있어서,The method according to claim 1, 상기 MEK 억제제가Wherein the MEK inhibitor is 2,4-비스-(2-클로로-4-요오도-페닐아미노)-3-플루오로-5-니트로-벤조산,2,4-bis- (2-chloro-4-iodo-phenylamino) -3-fluoro-5-nitro- 5-[3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-[1,3,4]옥사디아졸-2-일아민,Methyl-phenylamino] -phenyl] - [l, 3,4] oxadiazol-2-ylamine, 5-[4-플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-[1,3,4]옥사디아졸-2-올,2- [4-iodo-2-methyl-phenylamino] -phenyl] - [1,3,4] oxadiazol- (2,3-디플루오로-6-[1,3,4]옥사디아졸-2-일-페닐)-(4-요오도-2-메틸-페닐)-아민,(2,3-difluoro-6- [1,3,4] oxadiazol-2-yl-phenyl) - (4-iodo-2- methyl- phenyl) 5-[3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-[1,3,4]옥사디아졸-2-티올,Methyl-phenylamino) -phenyl] - [1,3,4] oxadiazole-2-thiol, 5-[3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-4H-[1,2,4]트리아졸-3-일아민, 및5- [3,4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -4 H - [1,2,4] triazol-3-ylamine, and 5-[3,4-디플루오로-2-(4-요오도-2-메틸-페닐아미노)-페닐]-4H-[1,2,4]트리아졸-3-티올로부터 선택된 구조를 갖는 방법.5- [3,4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl] -4 H - [1,2,4] triazole-3-thiol a structure selected from / RTI &gt; 제 1 항에 있어서,The method according to claim 1, 상기 MEK 억제제가 2,4-비스-(2-클로로-4-요오도-페닐아미노)-3-플루오로-5-니트 로-벤조산 구조를 갖는 방법.Wherein the MEK inhibitor has a 2,4-bis- (2-chloro-4-iodo-phenylamino) -3-fluoro-5-nitro-benzoic acid structure.
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