AMIDE SUBSTITUTED INDOLE COMPOUNDS USEFUL AS TLR INHIBITORSThe invention discloses a compound of a formula (I), and N-oxides or salts thereof, wherein G, L2, R1, R5, R9, R10, and n are defined herein. Also disclosed are methods of using such compounds as inhibitors of signaling through Toll-like receptor 7, or 8, or 9, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating inflammatory and autoimmune diseases.A compound of formula (i) an n-oxide or salt thereof, wherein: g is: (i)(ii)(iii)(iv) a 9-membered heterocycle selected from: (v) a 10-membered heterocycle selected from: l2is a bond or- (cr) xrx)1-3-；r1is h, cl, -cn, c 1-4alkyl radical, c 1-3fluoroalkyl radical, c 1-3hydroxyalkyl radical, c 1-3hydroxy-fluoroalkyl, -cr v＝ch2、c3-6cycloalkyl, -ch 2(c3-6cycloalkyl), -c (o) o (c) 1-3alkyl) or tetrahydropyranyl; each r is 2independently halogen, -cn, -oh, -no 2、c1-4alkyl radical, c 1-2fluoroalkyl radical, c 1-2cyanoalkyl, c 1-3hydroxyalkyl radical, c 1-3aminoalkyl, -o (ch) 2)1-2oh、-(ch2)0-4o(c1-4alkyl group), c 1-3fluoroalkoxy, - (ch) 2)1-4o(c1-3alkyl), -o (ch) 2)1-2oc(o)(c1-3alkyl), -o (ch) 2)1-2nrxrx、-c(o)o(c1-3alkyl), - (ch) 2)0-2c(o)nryry、-c(o)nrx(c1-5hydroxyalkyl), -c (o) nr x(c2-6alkoxyalkyl), -c (o) nr) x(c3-6cycloalkyl), -nr- yry、-nry(c1-3fluoroalkyl group), -nr y(c1-4hydroxyalkyl), -nr xch2(phenyl), -nr xs(o)2(c3-6cycloalkyl), -nr- xc(o)(c1-3alkyl), -nr- xch2(c3-6cycloalkyl), -s (o) 2(c1-3alkyl), - (ch) 2)0-2(c3-6cycloalkyl), - (ch) 2)0-2(phenyl), morpholinyl, dioxothiomorpholinyl, dimethylpyrazolyl, methylpiperidinyl, methylpiperazinyl, amino-oxadiazolyl, imidazolyl, triazolyl or-c (o) (thiazolyl); r2ais c 1-6alkyl radical, c 1-3fluoroalkyl radical, c 1-6hydroxyalkyl radical, c 1-3aminoalkyl, - (ch) 2)0-4o(c1-3alkyl group), c 3-6cycloalkyl, - (ch) 2)1-3c(o)nrxrx、-ch2(c3-6cycloalkyl), -ch 2(phenyl), tetrahydrofuranyl, tetrahydropyranyl or phenyl; each r is 2bindependently h, halogen, -cn, -nr xrx、c1-6alkyl radical, c 1-3fluoroalkyl radical, c 1-3hydroxyalkyl radical, c 1-3fluoroalkoxy, - (ch) 2)0-2o(c1-3alkyl), - (ch) 2)0-3c(o)nrxrx、-(ch2)1-3(c3-6cycloalkyl), -c (o) o (c) 1-3alkyl), -c (o) nr x(c1-3alkyl), -cr x＝crxrxor-cr x＝ch(c3-6cycloalkyl groups); r2cis r 2aor r 2b；r2dis r 2aor r 2b(ii) a with the proviso that r 2cand r 2done is r 2aand r is 2cand r 2dthe other of (a) is r 2b；each r is 5independently f, cl, -cn, c 1-3alkyl radical, c 1-2fluoroalkyl or-och 3；r9is c 1-6alkyl radical, c 1-6hydroxyalkyl radical, c 1-6hydroxy fluoroalkyl radical, c 1-3aminoalkyl, - (ch) 2)1-2o(c1-3alkyl), - (ch) 2)1-3nrxrx、-(ch2)1-2c(o)nrxrx、-(ch2)1-3s(o)2oh、-(crxrx)1-3nrxs(o)2(c1-2alkyl) or- (ch) 2)0-3r9a；r9ais c 3-7cycloalkyl, furyl, phenyl, piperazinyl, piperidinyl, pyrazolyl, pyridinyl, pyrrolidinyl, quinuclidinyl, thiazolyl or octahydrocyclopenta [ c ] ]pyrrolyl, each substituted with 0 to 3 substituents independently selected from f, cl, -oh, c 1-4alkyl radical, c 1-3hydroxyalkyl radical, c 1-3hydroxy fluoroalkyl radical, c 1-3aminoalkyl, -nr yryoxetanyl, phenyl, piperazinyl, piperidinyl and pyrrolidinyl; r10is h, c 1-4alkyl, - (ch) 2)1-3o(c1-2alkyl) or c 3-6a cycloalkyl group; or r 9and r 10together with the nitrogen atom to which they are attached form a heterocyclic ring selected from azabicyclo [3.1.1 ]heptylalkyl, azaspiro [5.5 ]undecyl, diazabicyclo [2.2.1 ]heptylalkyl, diazabicyclo [3.1.1 ]heptylalkyl, diazabicyclo [3.2.0 ]heptylalkyl, diazaspiro [3.5 ] ]nonanyl, diazaspiro [4.4 ]nonanyl, diazaspiro [4.5 ] ]decyl, diazepanyl, indolinyl, morpholinyl, octahydropyrrolo [3,4-c ]pyrrolyl, piperazinonyl, piperazinyl, piperidinyl and pyrrolidinyl each substituted with 0 to 3r 10asubstitution; each r is 10aindependently selected from c 1-4alkyl radical, c 1-4hydroxyalkyl, - (ch) 2)1-3o(c1-3alkyl), - (ch) 2)1-3nrxrx、-(ch2)1-2c(o)nrxrx、-(ch2)1-2(methyltriazolyl), -ch 2ch2(phenyl), -ch 2ch2(morpholinyl), -c (o) (c) 1-2alkyl), -c (o) nr yry、-c(o)ch2nryry、-nryry、-nhc(o)(c1-3alkyl), -c (o) (furyl), -o (piperidyl), -c (o) ch 2(diethylcarbamoylpiperidyl), methylpiperazinyl, piperidyl, methylpiperidinyl, diethylcarbamoylpiperidyl, isopropylpiperidyl, pyridyl, trifluoromethylpyridyl, pyrimidyl and dihydrobenzo [ d ]an imidazolonyl group; rvis h, c 1-2alkyl or c 1-2a fluoroalkyl group; each r is xindependently is h or-ch 3；each r is yindependently is h or c 1-6an alkyl group; n is 0, 1 or 2; and p is 0, 1, 2, 3 or 4.
TLR 억제제로서 유용한 아미드 치환된 인돌 화합물[이미지], 그의 N-옥시드, 또는 염이 개시된다: 상기 식에서, G, L2, R1, R5, R9, R10, 및 n 는 본원에 정의된다. 또한 톨-유사 수용체 7, 또는 8, 또는 9를 통한 신호전달의 억제제로서 이러한 화합물을 사용하는 방법 및 이러한 화합물을 포함하는 제약 조성물이 개시된다. 이들 화합물은 염증성 및 자가면역 질환을 치료하는데 유용하다.하기 화학식 I의 화합물, 그의 N-옥시드, 또는 염:[이미지]상기 식에서,G는:(i) [이미지](ii) [이미지](iii) [이미지](iv) 하기로부터 선택된 9-원 헤테로시클릭 고리:[이미지][이미지][이미지][이미지];또는(v) 하기로부터 선택된 10-원 헤테로시클릭 고리:[이미지]이고;L2는 결합 또는 -(CRxRx)1-3-이고;R1은 H, Cl, -CN, C1-4 알킬, C1-3 플루오로알킬, C1-3 히드록시알킬, C1-3 히드록시-플루오로알킬, -CRv=CH2, C3-6 시클로알킬, -CH2(C3-6 시클로알킬), -C(O)O(C1-3 알킬), 또는 테트라히드로피라닐이고;각각의 R2는 독립적으로 할로, -CN, -OH, -NO2, C1-4 알킬, C1-2 플루오로알킬, C1-2 시아노알킬, C1-3 히드록시알킬, C1-3 아미노알킬, -O(CH2)1-2OH, -(CH2)0-4O(C1-4 알킬), C1-3 플루오로알콕시, -(CH2)1-4O(C1-3 알킬), -O(CH2)1-2OC(O)(C1-3 알킬), -O(CH2)1-2NRxRx, -C(O)O(C1-3 알킬), -(CH2)0-2C(O)NRyRy, -C(O)NRx(C1-5 히드록시알킬), -C(O)NRx(C2-6 알콕시알킬), -C(O)NRx(C3-6 시클로알킬), -NRyRy, -NRy(C1-3 플루오로알킬), -NRy(C1-4 히드록시알킬), -NRxCH2(페닐), -NRxS(O)2(C3-6 시클로알킬), -NRxC(O)(C1-3 알킬), -NRxCH2(C3-6 시클로알킬), -S(O)2(C1-3 알킬), -(CH2)0-2(C3-6 시클로알킬), -(CH2)0-2(페닐), 모르폴리닐, 디옥소티오모르폴리닐, 디메틸 피라졸릴, 메틸피페리디닐, 메틸피페라지닐, 아미노-옥사디아졸릴, 이미다졸릴, 트리아졸릴, 또는 -C(O)(티아졸릴)이고;R2a는 C1-6 알킬, C1-3 플루오로알킬, C1-6 히드록시알킬, C1-3 아미노알킬, -(CH2)0-4O(C1-3 알킬), C3-6 시클로알킬, -(CH2)1-3C(O)NRxRx, -CH2(C3-6 시클로알킬), -CH2(페닐), 테트라히드로푸라닐, 테트라히드로피라닐, 또는 페닐이고;각각의 R2b는 독립적으로 H, 할로, -CN, -NRxRx, C1-6 알킬, C1-3 플루오로알킬, C1-3 히드록시알킬, C1-3 플루오로알콕시, -(CH2)0-2O(C1-3 알킬), -(CH2)0-3C(O)NRxRx, -(CH2)1-3(C3-6 시클로알킬), -C(O)O(C1-3 알킬), -C(O)NRx(C1-3 알킬), -CRx=CRxRx, 또는 -CRx=CH(C3-6 시클로알킬)이고;R2c는 R2a 또는 R2b이고;R2d는 R2a 또는 R2b이고; 단 R2c 및 R2d 중 하나는 R2a이고, R2c 및 R2d 중 다른 하나는 R2b이고;각각의 R5는 독립적으로 F, Cl, -CN, C1-3 알킬, C1-2 플루오로알킬, 또는 -OCH3이고;R9는 C1-6 알킬, C1-6 히드록시알킬, C1-6 히드록시 플루오로알킬, C1-3 아미노알킬, -(CH2)1-2O(C1-3 알킬), -(CH2)1-3NRxRx, -(CH2)1-2C(O)NRxRx, -(CH2)1-3S(O)2OH, -(CRxRx)1-3NRxS(O)2(C1-2 알킬), 또는 -(CH2)0-3R9a이고;R9a는 C3-7 시클로알킬, 푸라닐, 페닐, 피페라지닐, 피페리디닐, 피라졸릴, 피리디닐, 피롤리디닐, 퀴누클리디닐, 티아졸릴, 또는 옥타히드로시클로펜타[c]피롤릴이고, 각각은 F, Cl, -OH, C1-4 알킬, C1-3 히드록시알킬, C1-3 히드록시 플루오로알킬, C1-3 아미노알킬, -NRyRy, 옥세타닐, 페닐, 피페라지닐, 피페리디닐, 및 피롤리디닐로부터 독립적으로 선택된 0 내지 3개의 치환기로 치환되고;R10은 H, C1-4 알킬, -(CH2)1-3O(C1-2 알킬), 또는 C3-6 시클로알킬이거나;또는 R9 및 R10은 이들이 부착되어 있는 질소 원자와 함께 아자비시클로[3.1.1]헵타닐, 아자스피로[5.5]운데카닐, 디아자비시클로[2.2.1]헵타닐, 디아자비시클로[3.1.1]헵타닐, 디아자비시클로[3.2.0]헵타닐, 디아자스피로[3.5]노나닐, 디아자스피로[4.4]노나닐, 디아자스피로[4.5]데카닐, 디아제파닐, 인돌리닐, 모르폴리닐, 옥타히드로피롤로[3,4-c]피롤릴, 피페라지노닐, 피페라지닐, 피페리디닐, 및 피롤리디닐로부터 선택된 헤테로시클릭 고리를 형성하고, 각각은 0 내지 3개의 R10a로 치환되고;각각의 R10a는 독립적으로 C1-4 알킬, C1-4 히드록시알킬, -(CH2)1-3O(C1-3 알킬), -(CH2)1-3NRxRx, -(CH2)1-2C(O)NRxRx, -(CH2)1-2(메틸트리아졸릴), -CH2CH2(페닐), -CH2CH2(모르폴리닐), -C(O)(C1-2 알킬), -C(O)NRyRy, -C(O)CH2NRyRy, -NRyRy, -NHC(O)(C1-3 알킬), -C(O)(푸라닐), -O(피페리디닐), -C(O)CH2(디에틸카르바모일피페리디닐), 메틸피페라지닐, 피페리디닐, 메틸피페리디닐, 디에틸카르바모일피페리디닐, 이소프로필피페리디닐, 피리디닐, 트리플루오로메틸피리디닐, 피리미디닐, 및 디히드로벤조[d]이미다졸로닐로부터 선택되고;Rv는 H, C1-2 알킬, 또는 C1-2 플루오로알킬이고;각각의 Rx는 독립적으로 H 또는 -CH3이고;각각의 Ry는 독립적으로 H 또는 C1-6 알킬이고;n은 0, 1, 또는 2이고;p는 0, 1, 2, 3, 또는 4이다.