SUBSTITUTED INDOLE COMPOUNDS USEFUL AS TLR INHIBITORSDisclosed are compounds of Formula (I) N-oxides, or salts thereof, wherein G, A, R1, R5, and n are defined herein. Also disclosed are methods of using such compounds as inhibitors of signaling throughToll-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 a salt thereof,wherein:g is:(i)(ii)(iii)(iv) a 9-membered heterocycle selected from:or(v) a 10-membered heterocycle selected from:a is as follows:(i)-(crxrx)1-3r11、c1-3aminoalkyl, - (cr)xrx)1-3nrxc(o)r11、-(crxrx)1-2nrxc(o)(ch2)1-2(piperidinyl), - (cr)xrx)1-2nrxc(o)o(ch2)1-2(piperidinyl) or- (cr)xrx)1-2nrxc(o)(ch2)1-2nrxrx；(ii)-crxr12r13wherein r is12and r13together with the carbon atom to which they are attached form a cyclic group selected from azabicyclo [4.1.1]octyl, azepanyl, azetidinyl, c3-7cycloalkyl, diazacycloheptane, diazaspiro [4.5]]decanoyl, morpholinyl, octahydrocyclopenta [ c ]]pyrrolyl, piperazinyl, piperidinyl, pyrrolidinyl or quinuclidinyl, each of which is substituted with 0 to 4r12asubstitution; or(iii)-crx＝crx(piperidinyl);r1is h, cl, -cn, c1-4alkyl radical, c1-3fluoroalkyl radical, c1-3hydroxyalkyl radical, c1-3hydroxy-fluoroalkyl, -crv＝ch2、c3-6cycloalkyl, -ch2(c3-6cycloalkyl), -c (o) o (c)1-3alkyl) or tetrahydropyranyl;each r is2independently halogen, -cn, -oh, -no2、c1-4alkyl radical, c1-2fluoroalkyl radical, c1-2cyanoalkyl, c1-3hydroxyalkyl radical, c1-3aminoalkyl, -o (ch)2)1-2oh、-(ch2)0-4o(c1-4alkyl group), c1-3fluoroalkoxy, - (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) nrx(c2-6alkoxyalkyl), -c (o) nrx(c3-6cycloalkyl), -nr-yry、-nry(c1-3fluoroalkyl group), -nry(c1-4hydroxyalkyl), -nrxch2(phenyl), -nrxs(o)2(c3-6cycloalkyl), -nr-xc(o)(c1-3alkyl), -nr-xch2(cyclopropyl), -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 c1-6alkyl radical, c1-3fluoroalkyl radical, c1-6hydroxyalkyl radical, c1-3aminoalkyl, - (ch)2)0-4o(c1-3alkyl group), c3-6cycloalkyl, - (ch)2)1-3c(o)nrxrx、-ch2(c3-6cycloalkyl), -ch2(phenyl), tetrahydrofuranyl, tetrahydropyranyl or phenyl;each r is2bindependently h, halogen, -cn, -nrxrx、c1-6alkyl radical, c1-3fluoroalkyl radical, c1-3hydroxyalkyl radical, c1-3fluoroalkoxy, - (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) nrx(c1-3alkyl), -crx＝crxrxor-crx＝ch(c3-6cycloalkyl groups);r2cis r2aor r2b；r2dis r2aor r2b(ii) a with the proviso that r2cand r2done is r2aand r is2cand r2dis r2b；each r is5independently f, cl, -cn, c1-3alkyl radical, c1-2fluoroalkyl or-och3；r11is azetidinyl, azaspiro [3.5]]nonyl, thiomorpholinyl, hexahydropyrrolo [3, 4-c)]pyrrolyl, morpholinyl, piperazinyl, piperidinyl, pyridinyl or pyrrolidinyl, each of which is substituted with 0 to 3 substituents independently selected from halogen, -cn, c1-4alkyl radical, c1-3aminoalkyl, - (ch)2)1-2(phenyl), -c (o) ch2nrxrx、c1-5hydroxyalkyl, - (ch)2)1-2c(o)nrxrx、-(ch2)1-2s(o)2(c1-3alkyl), - (ch)2)1-2s(o)(c1-3alkyl), oxetanyl, tetrahydrofuranyl and tetrahydropyranyl;each r is12aindependently f, cl, -oh, c1-6alkyl radical, c1-4fluoroalkyl radical, c1-4cyanoalkyl, c1-6hydroxyalkyl, - (ch)2)1-2o(c1-3alkyl), - (ch)2)1-2c(o)nrxrx、-(ch2)1-2s(o)2(c1-2alkyl), - (ch)2)1-2nrxhs(o)2(c1-2alkyl), - (ch)2)1-2nrxrx、c1-3alkoxy, -nryry、-nrx(c1-3fluoroalkyl group), -nrx(ch2ch2o(c1-3alkyl)), -nrx(c1-2cyanoalkyl), -nrxch2nrxrx、-nrx(c1-4hydroxyalkyl), -nrx(ch2c(o)nrxrx)、-nrx(c1-3alkoxy), -nrxch2ch2s(o)2(c1-2alkyl), -nr-xc(o)ch3、-nrxc(o)(c1-2fluoroalkyl group), -nrxc(o)crxrxnrxrx、-nrxc(o)ch2nryry、-nrxc(o)ch2nrx(c1-4hydroxyalkyl), -nrx(ch2)1-2c(o)nrxrx、-nrxs(o)2(c1-2alkyl), -c (o) (c)1-5alkyl), -c (o) (ch)2)1-3o(c1-2alkyl), -c (o) crxrxnryry、r12b、-crxrxr12b、-c(o)r12b、-crxrxr12b、-c(o)crxrxnrxr12b、-c(o)nrxr12b、-nrxc(o)crxrxr12b、-nrxr12b、-nrxcrxrxr12b、-nrxc(o)crxrxnrxr12b、-nrxc(o)crxrxnrxch2r12b、-nrxcrxrxc(o)nrxr12bor-or12b；r12bis azetidinyl, c3-6cycloalkyl, diazabicyclo [2.2.1]heptylalkyl group, dioxolanyl group, tetrahydrothiopyranyl dioxide group, thiomorpholinyl group, imidazolyl group, morpholinyl group, thiomorpholinyl group, and the like,octahydrocyclopenta [ c ] s]pyrrolyl, octahydropyrrolo [3, 4-c)]pyrrolyl, oxaazaspiro [3.3]heptenyl, oxetanyl, phenyl, piperazinyl, piperazinonyl, piperidinyl, pyridinyl, pyrrolidinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl or triazolyl, each of which is substituted with 0 to 4 substituents independently selected from f, cl, -oh, c1-4alkyl radical, c1-3fluoroalkyl radical, c1-3hydroxyalkyl radical, c1-3aminoalkyl radical, c1-4alkoxy, - (ch)2)1-2o(c1-3alkyl), -nr-xrxand-c (o) nrxrx；rvis h, c1-2alkyl or c1-2a fluoroalkyl group;each r isxindependently is h or-ch3；each r isyindependently f, cl, -cn, c1-3alkyl radical, c1-3fluoroalkyl radical, c1-3alkoxy, -nrxc(o)(c1-3alkyl), -c (o) nrxrx、c3-6cycloalkyl, piperidinyl or morpholinyl;n is 0, 1 or 2; and isp is 0, 1,2,3 or 4.
TLR 억제제로서 유용한 치환된 인돌 화합물하기 화학식 I의 화합물, 그의 N-옥시드 또는 염이 개시된다:[이미지] 상기 식에서, G, A, R1, R5, 및 n은 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;A는:(i) -(CRxRx)1-3R11, C1-3 아미노알킬, -(CRxRx)1-3NRxC(O)R11, -(CRxRx)1-2NRxC(O)(CH2)1-2(피페리디닐), -(CRxRx)1-2NRxC(O)O(CH2)1-2(피페리디닐), 또는 -(CRxRx)1-2NRxC(O)(CH2)1-2NRxRx;(ii) -CRxR12R13 (여기서 R12 및 R13은 이들이 부착되어 있는 탄소 원자와 함께 아자비시클로[4.1.1]옥타닐, 아제파닐, 아제티디닐, C3-7 시클로알킬, 디아제파닐, 디아자스피로[4.5]데카노닐, 모르폴리닐, 옥타히드로시클로펜타[c]피롤릴, 피페라지닐, 피페리디닐, 피롤리디닐, 또는 퀴누클리디닐로부터 선택된 시클릭 기를 형성하고, 각각은 0 내지 4개의 R12a로 치환됨); 또는(iii) -CRx=CRx(피페리디닐)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(시클로프로필), -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;R11은 아제티디닐, 아자스피로[3.5]노나닐, 디옥시도티오모르폴리닐, 헥사히드로피롤로[3,4-c]피롤릴, 모르폴리닐, 피페라지닐, 피페리디닐, 피리디닐, 또는 피롤리디닐이고, 각각은 할로, -CN, C1-4 알킬, C1-3 아미노알킬, -(CH2)1-2(페닐), -C(O)CH2NRxRx, C1-5 히드록시알킬, -(CH2)1-2C(O)NRxRx, -(CH2)1-2S(O)2(C1-3 알킬), -(CH2)1-2S(O)(C1-3 알킬), 옥세타닐, 테트라히드로푸라닐, 및 테트라히드로피라닐로부터 독립적으로 선택된 0 내지 3개의 치환기로 치환되고;각각의 R12a는 독립적으로 F, Cl, -OH, C1-6 알킬, C1-4 플루오로알킬, C1-4 시아노알킬, C1-6 히드록시알킬, -(CH2)1-2O(C1-3 알킬), -(CH2)1-2C(O)NRxRx, -(CH2)1-2S(O)2(C1-2 알킬), -(CH2)1-2NRxHS(O)2(C1-2 알킬), -(CH2)1-2NRxRx, C1-3 알콕시, -NRyRy, -NRx(C1-3 플루오로알킬), -NRx(CH2CH2O(C1-3 알킬)), -NRx(C1-2 시아노알킬), -NRxCH2NRxRx, -NRx(C1-4 히드록시알킬), -NRx(CH2C(O)NRxRx), -NRx(C1-3 알콕시), -NRxCH2CH2S(O)2(C1-2 알킬), -NRxC(O)CH3, -NRxC(O)(C1-2 플루오로알킬), -NRxC(O)CRxRxNRxRx, -NRxC(O)CH2NRyRy, -NRxC(O)CH2NRx(C1-4 히드록시알킬), -NRx(CH2)1-2C(O)NRxRx, -NRxS(O)2(C1-2 알킬), -C(O)(C1-5 알킬), -C(O)(CH2)1-3O(C1-2 알킬), -C(O)CRxRxNRyRy, R12b, -CRxRxR12b, -C(O)R12b, -CRxRxR12b, -C(O)CRxRxNRxR12b, -C(O)NRxR12b, -NRxC(O)CRxRxR12b, -NRxR12b, -NRxCRxRxR12b, -NRxC(O)CRxRxNRxR12b, -NRxC(O)CRxRxNRxCH2R12b, -NRxCRxRxC(O)NRxR12b, 또는 -OR12b이고;R12b는 아제티디닐, C3-6 시클로알킬, 디아자비시클로[2.2.1]헵타닐, 디옥솔라닐, 디옥시도테트라히드로티오피라닐, 디옥시도티오모르폴리닐, 이미다졸릴, 모르폴리닐, 옥타히드로시클로펜타[c]피롤릴, 옥타히드로피롤로[3,4-c]피롤릴, 옥사아자스피로[3.3]헵타닐, 옥세타닐, 페닐, 피페라지닐, 피페라지노닐, 피페리디닐, 피리디닐, 피롤리디닐, 퀴누클리디닐, 테트라히드로푸라닐, 테트라히드로피라닐, 또는 트리아졸릴이고, 각각은 F, Cl, -OH, C1-4 알킬, C1-3 플루오로알킬, C1-3 히드록시알킬, C1-3 아미노알킬, C1-4 알콕시, -(CH2)1-2O(C1-3 알킬), -NRxRx, 및 -C(O)NRxRx로부터 독립적으로 선택된 0 내지 4개의 치환기로 치환되고;Rv는 H, C1-2 알킬, 또는 C1-2 플루오로알킬이고;각각의 Rx는 독립적으로 H 또는 -CH3이고;각각의 Ry는 독립적으로 F, Cl, -CN, C1-3 알킬, C1-3 플루오로알킬, C1-3 알콕시, -NRxC(O)(C1-3 알킬), -C(O)NRxRx, C3-6 시클로알킬, 피페리디닐, 또는 모르폴리닐이고;n은 0, 1, 또는 2이고;p는 0, 1, 2, 3, 또는 4이다.