SULFONYL UREA COMPOUNDS AS INHIBITORS OF INTERLEUKIN-1 ACTIVITYThe present disclosure relates to novel sulfonyl urea compounds and related compounds useful in treating a disorder responsive to modulation of cytokines such as IL-1[beta] and IL-18, modulation of NLRP3 or inhibition of the activation of NLRP3 or related components of the inflammatory process.A compound having the structure of formula (i),or a pharmaceutically acceptable salt, solvate, isomer, prodrug or tautomer thereof, wherein:r1is composed ofr1zis h, d, halogen, -cn, -no2、-sr7a、-or7a、-c(o)r7b、-p(o)r7br8b、-s(o)2r7b、-s(o)r7b、-nr7ar8a、-nr7ac(o)r8a、-nr7ac(o)or8a、-nr7ac(o)nr8a、-nr7as(o)2r8a、c1-c6alkyl radical, c2-c6alkenyl radical, c4-c8cycloalkenyl radical, c2-c6alkynyl, c3-c10cycloalkyl radical, c6aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; wherein said c1-c6alkyl radical, c2-c6alkenyl radical, c4-c8cycloalkenyl radical, c2-c6alkynyl, c3-c10cycloalkyl radical, c6aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of: d. -cn, halogen, c 1-c6alkyl, -or7a、-c(o)r7b、-p(o)r7br8b、-s(o)2r7b、-s(o)r7b、-nr7ar8a、-nr7ac(o)r8a、-nr7ac(o)or8a、-nr7ac(o)nr8a、-nr7as(o)2r8a、c3-c10cycloalkyl radical, c6aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;r1a、r1b、r1c、r1d、r1e、r1f、r1gand r1heach independently selected from h, d, halogen, -cn, -no2、-sr11a、-or11a、-c(o)r11b、-p(o)r11br12b、-s(o)2r11b、-s(o)r11b、-nr11ar12a、-nr11ac(o)r12a、-nr11ac(o)or12a、-nr11ac(o)nr12a、-nr11as(o)2r12a、c1-c6alkyl radical, c2-c6alkenyl radical, c4-c8cycloalkenyl radical, c2-c6alkynyl, c3-c10cycloalkyl radical, c6aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; wherein said c1-c6alkyl radical, c2-c6alkenyl radical, c4-c8cycloalkenyl radical, c2-c6alkynyl, c3-c10cycloalkyl radical, c6aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of: d. -cn, halogen, c1-c6alkyl, -or11a、-c(o)r11b、-p(o)r11br12b、-s(o)2r11b、-s(o)r11b、-nr11ar12a、-nr11ac(o)r12a、-nr11ac(o)or12a、-nr11ac(o)nr12a、-nr11as(o)2r12a、c3-c10cycloalkyl radical, c6aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl; orwhen the following group r1a、r1b、r1c、r1d、r1e、r1f、r1gand r1hwhen present, two of the groups together with the atom to which they are attached may form c3-c10cycloalkyl or 3-7 membered heterocyclyl; wherein said c3-c10the cycloalkyl and 3-7 membered heterocyclyl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of: d. -cn, halogen, c1-c6alkyl, -or13a、-c(o)r13b、-p(o)r13br14b、-s(o)2r13b、-s(o)r13b、-nr13ar14a、-nr13ac(o)r14a、-nr13ac(o)or14a、-nr13ac(o)nr14aand-nr13as(o)2r14a(ii) a orwhen two geminal radicals r1aand r1b、r1cand r1d、r1eand r1for r1gand r1hwhen present, an oxo group may be formed;r2selected from the group consisting of: c1-c6alkyl radical, c3-c10cycloalkyl, 5-7 membered heterocyclyl, 5-membered heteroaryl, 6-membered heteroaryl containing 6-11 ring atoms or-nr 2gr2h(ii) a wherein said c1-c6alkyl radical, c3-c10cycloalkyl, 5-7 membered heterocyclyl, 5-membered heteroaryl, and 6-membered heteroaryl containing 6-11 ring atoms are independently unsubstituted or substituted with one or more substituents, or alternatively when two substituents are present, wherein the substituents together with the atom to which they are attached may form a ring;r2gand r2heach independentlyis h, d, c1-c6alkyl radical, c3-c10cycloalkyl radical, c6aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl, wherein said c1-c6alkyl radical, c3-c10cycloalkyl radical, c6aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of: d. -cn, halogen, c1-c6alkyl radical, c1-c6haloalkyl, c2-c6alkenyl, oxo, -or21a、-c(o)r21b、-p(o)r21br22b、-s(o)2r21b、-s(o)r21b、-nr21ar22a、-nr21ac(o)r22a、-nr21ac(o)or22a、-nr21ac(o)nr22a、-nr21as(o)2r22a、-(ch2)1-4c3-c10cycloalkyl radical, c3-c10cycloalkyl radical, c6aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;r7a、r8a、r11a、r12a、r13a、r14a、r21aand r22ah, d, c independently at each occurrence1-c8alkyl radical, c2-c8alkenyl radical, c2-c8alkynyl, c3-c10cycloalkyl radical, c4-c8cycloalkenyl radical, c6aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; wherein said c1-c8alkyl radical, c2-c8alkenyl radical, c2-c8alkynyl, c3-c10cycloalkyl radical, c4-c8cycloalkenyl radical, c6aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of: d. -cn, halogen, c 1-c6alkyl, -oh, -o-c1-c6alkyl, -nh2、-nh(c1-c6alkyl), -n (c)1-c6alkyl radical)2、c3-c10cycloalkyl radical, c6aryl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl; and isr7b、r8b、r11b、r12b、r13b、r14b、r21band r22bindependently at each occurrence h, d, -oh, -o (c)1-c6alkyl), -nh2、-nh(c1-c6alkyl), -n (c)1-c6alkyl radical)2、-nhs(o)2ch3、c1-c8alkyl radical, c2-c8alkenyl radical, c2-c8alkynyl, c3-c10cycloalkyl radical, c4-c8cycloalkenyl radical, c6aryl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; wherein said c1-c8alkyl radical, c2-c8alkenyl rad...
인터루킨-1 활성의 저해제로서의 설포닐유레아 화합물본 개시물은 시토킨, 가령 IL-1β 및 IL-18의 조절에 반응성인 장애의 치료, NLRP3의 조절 또는 NLRP3 또는 염증 과정의 관련 성분의 활성화의 저해에 유용한 신규한 설포닐유레아 화합물 및 관련 화합물에 관한 것이다.식 (I)의 구조를 갖는 화합물, 또는 그의 약제학적으로 허용가능한 염, 용매화물, 이성질체, 프로드럭, 또는 호변체:[이미지](I)상기 식에서,R1은, [이미지], [이미지], 또는 [이미지]이고;R1z은 H, D, 할로겐, -CN, -NO2, -SR7a, -OR7a, -C(O)R7b, -P(O)R7bR8b, -S(O)2R7b, -S(O)R7b, -NR7aR8a, -NR7aC(O)R8a, -NR7aC(O)OR8a, -NR7aC(O)NR8a, -NR7aS(O)2R8a, C1-C6알킬, C2-C6알케닐, C4-C8시클로알케닐, C2-C6알키닐, C3-C10시클로알킬, C6아릴, 3-7-원 헤테로시클릴, 또는 5-6-원 헤테로아릴이고; 여기서 C1-C6알킬, C2-C6알케닐, C4-C8시클로알케닐, C2-C6알키닐, C3-C10시클로알킬, C6아릴, 3-7-원 헤테로시클릴, 및 5-6 원 헤테로아릴은 독립적으로 치환되지 않거나 D, -CN, 할로겐, C1-C6알킬, -OR7a, -C(O)R7b, -P(O)R7bR8b, -S(O)2R7b, -S(O)R7b, -NR7aR8a, -NR7aC(O)R8a, -NR7aC(O)OR8a, -NR7aC(O)NR8a, -NR7aS(O)2R8a, C3-C10시클로알킬, C6아릴, 3-7-원 헤테로시클릴, 및 5-6 원 헤테로아릴로 구성된 그룹으로부터 선택된 하나 이상의 치환기로 치환되고;각각의 R1a, R1b, R1c, R1d, R1e, R1f, R1g, 및 R1h는 H, D, 할로겐, -CN, -NO2, -SR11a, -OR11a, -C(O)R11b, -P(O)R11bR12b, -S(O)2R11b, -S(O)R11b, -NR11aR12a, -NR11aC(O)R12a, -NR11aC(O)OR12a, -NR11aC(O)NR12a, -NR11aS(O)2R12a, C1-C6알킬, C2-C6알케닐, C4-C8시클로알케닐, C2-C6알키닐, C3-C10시클로알킬, C6아릴, 3-7-원 헤테로시클릴, 또는 5-6-원 헤테로아릴로부터 독립적으로 선택되고; 여기서 C1-C6알킬, C2-C6알케닐, C4-C8시클로알케닐, C2-C6알키닐, C3-C10시클로알킬, C6아릴, 3-7-원 헤테로시클릴, 및 5-6 원 헤테로아릴은 독립적으로 치환되지 않거나 D, -CN, 할로겐, C1-C6알킬, -OR11a, -C(O)R11b, -P(O)R11bR12b, -S(O)2R11b, -S(O)R11b, -NR11aR12a, -NR11aC(O)R12a, -NR11aC(O)OR12a, -NR11aC(O)NR12a, -NR11aS(O)2R12a, C3-C10시클로알킬, C6아릴, 3-7-원 헤테로시클릴, 및 5-6 원 헤테로아릴로 구성된 그룹으로부터 선택된 하나 이상의 치환기로 치환되거나;R1a, R1b, R1c, R1d, R1e, R1f, R1g, 및 R1h 중의 두 개는, 존재한다면, 자신들이 부착된 원자와 함께 C3-C10시클로알킬 또는 3-7-원 헤테로시클릴을 형성할 수 있고; 여기서 C3-C10시클로알킬 및 3-7-원 헤테로시클릴은 독립적으로 치환되지 않거나 D, -CN, 할로겐, C1-C6알킬, -OR13a, -C(O)R13b, -P(O)R13bR14b, -S(O)2R13b, -S(O)R13b, -NR13aR14a, -NR13aC(O)R14a,-NR13aC(O)OR14a, -NR13aC(O)NR14a, 및 -NR13aS(O)2R14a로 구성된 그룹으로부터 선택된 하나 이상의 치환기로 치환되거나;두 같은자리 기 R1a 및 R1b; R1c 및 R1d; R1e 및 R1f; 또는 R1g 및 R1h는, 존재한다면, 옥소 기를 형성할 수 있고;R2는 C1-C6알킬, C3-C10시클로알킬, 5-7-원 헤테로시클릴, 5-원 헤테로아릴, 6-11 환형 원자를 함유하는 6-원 헤테로아릴, 또는 -NR2gR2h로 구성된 그룹으로부터 선택되고; 여기서 C1-C6알킬, C3-C10시클로알킬, 5-7-원 헤테로시클릴, 5-원 헤테로아릴, 및 6-11 환형 원자를 함유하는 6-원 헤테로아릴은 독립적으로 치환되지 않거나 하나 이상의 치환기로 치환되거나, 임의로 상기 치환기 중의 두 개는 존재한다면, 자신들이 부착된 원자와 함께 링을 형성할 수 있고;각각의 R2g 및 R2h는 독립적으로 H, D, C1-C6알킬, C3-C10시클로알킬, C6아릴, 3-7 원 헤테로시클릴, 또는 5-6 원 헤테로아릴이고, 여기서 C1-C6알킬, C3-C10시클로알킬, C6아릴, 3-7 원 헤테로시클릴, 및 5-6 원 헤테로아릴은 독립적으로 치환되지 않거나 D, -CN, 할로겐, C1-C6알킬, C1-C6할로알킬, C2-C6알케닐, 옥소, -OR21a, -C(O)R21b, -P(O)R21bR22b, -S(O)2R21b, -S(O)R21b, -NR21aR22a, -NR21aC(O)R22a, -NR21aC(O)OR22a, -NR21aC(O)NR22a, -NR21aS(O)2R22a, -(CH2)1-4C3-C10시클로알킬, C3-C10시클로알킬, C6아릴, 3-7-원 헤테로시클릴, 및 5-6-원 헤테로아릴로 구성된 그룹으로부터 선택된 하나 이상의 치환기로 치환되고;R7a, R8a, R11a, R12a, R13a, R14a, R21a, 및 R22a는 독립적으로, 각각의 경우, H, D, C1-C8알킬, C2-C8알케닐, C2-C8알키닐, C3-C10시클로알킬, C4-C8시클로알케닐, C6아릴, 3-7-원 헤테로시클릴, 또는 5-6-원 헤테로아릴이고; 여기서 C1-C8알킬, C2-C8알케닐, C2-C8알키닐, C3-C10시클로알킬, C4-C8시클로알케닐, C6아릴, 3-7-원 헤테로시클릴, 및 5-6-원 헤테로아릴은 독립적으로 치환되지 않거나 D, -CN, 할로겐, C1-C6알킬, -OH, -O-C1-C6알킬, -NH2, -NH(C1-C6알킬), -N(C1-C6알킬)2, C3-C10시클로알킬, C6아릴, 3-7-원 헤테로시클릴, 및 5-6 원 헤테로아릴로 구성된 그룹으로부터 선택된 하나 이상의 치환기로 치환되고;R7b, R8b, R11b, R12b, R13b, R14b, R21b, 및 R22b는 독립적으로, 각각의 경우, H, D, -OH, -O(C1-C6알킬), -NH2, -NH(C1-C6알킬), -N(C1-C6알킬)2, -NHS(O)2CH3, C1-C8알킬, C2-C8알케닐, C2-C8알키닐, C3-C10시클로알킬, C4-C8시클로알케닐, C6아릴, 3-7-원 헤테로시클릴, 또는 5-6-원 헤테로아릴이고; 여기서 C1-C8알킬, C2-C8알케닐, C2-C8알키닐, C3-C10시클로알킬, C4-C8시클로알케닐, C6아릴, 3-7-원 헤테로시클릴, 및 5-6-원 헤테로아릴은 독립적으로 치환되지 않거나 D, -CN, 할로겐, C1-C6알킬, -OH, -O-C1-C6알킬, -NH2, -NH(C1-C6알킬), -N(C1-C6알킬)2, C3-C10시클로알킬, C6아릴, 3-7-원 헤테로시클릴, 및 5-6 원 헤테로아릴로 구성된 그룹으로부터 선택된 하나 이상의 치환기로 치환됨.