PYRIMIDINYL-PYRIDYLOXY-NAPHTHYL COMPOUNDS AND METHODS OF TREATING IRE1-RELATED DISEASES AND DISORDERSDescribed herein are pyrimidinyl-pyridyloxy-naphthyl compounds with inositol requiring enzyme 1 (IRE1) modulation activity or function having the Formula (I) or (I') structure : or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, and with the substituents and structural features described herein. Also described are pharmaceutical compositions and medicaments that include theFormula (I) or (I') compounds, as well as methods of using such IRE1 modulators, alone and in combination with other therapeutic agents, for treating diseases or conditions that are mediated or dependent upon estrogen receptors.A compound having the formula i':or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:r1is c3-c12cycloalkyl radical, c3-c12heterocyclic group, c1-c12heteroaryl group, c6-c20aryl, - (c)1-c6alkyl diyl) - (c)3-c12cycloalkyl) or- (c)1-c6alkyl diyl) - (c)3-c12a heterocyclic group);r2is h, f, cl, -cn, -och3、-och2ch3or c1-c6an alkyl group;r3is h, -cn, c3-c12cycloalkyl radical, c3-c12heterocyclic group, c1-c12heteroaryl group, c6-c20aryl, -o- (c)1-c12heteroaryl), -o- (c)1-c6alkyl diyl) - (c)6-c20aryl), -n (r)8)(c1-c6alkyl), -nr-8c(o)r9、-nr8c(o)or9、-nr8c(o)nhr9、-nr8so2-(c1-c6alkyl), -nr-8so2-(c1-c6alkenyl), -nr8so2-(c3-c12cycloalkyl), -nr-8so2-(c1-c12heteroaryl), -nr8so2-(c1-c6alkyl diyl) - (c)3-c12cycloalkyl), -nr-8so2-(c1-c6alkyl diyl) - (c)3-c12heterocyclyl), -nr8so2-(c1-c6alkyl diyl) - (c)1-c12heteroaryl), -nr8so2-(c1-c6alkyl diyl) - (c)6-c20aryl), -nr-8so2nr8r9or-so2nr8r9；r4is h, -cn, c3-c12cycloalkyl radical, c3-c12heterocyclic group, c1-c12heteroaryl group, c6-c20aryl, -o- (c)1-c12heteroaryl), -o- (c)1-c6alkyl diyl) - (c)6-c20aryl), -nr-8r9、-nr8c(o)r9、-nr8c(o)or9、-nr8c(o)nhr9、-nr8so2-(c1-c6alkyl), -nr-8so2-(c1-c6alkenyl), -nr8so2-(c1-c12heteroaryl), -nr8so2-(c3-c12cycloalkyl), -nr-8so2-(c3-c12heterocyclyl), -nr8so2-(c1-c6alkyl diyl) (c3-c12cycloalkyl), -nr-8so2-(c1-c6alkyl diyl) - (c)3-c12heterocyclyl), -nr8so2-(c1-c6alkyl diyl) - (c)1-c12heteroaryl), -nr8so2-(c1-c6alkyl diyl) - (c)6-c20aryl), -nr-8so2nr8r9or-so2nr8r9；r5and r7each independently is h, f, cl, -cn, -ch2oh、-c(o)nh2、-oh、-och3、-och2ch3or c1-c6an alkyl group;n is 0, 1, 2 or 3;r6each independently is h, f, cl, br, i, -cn, -no2、-o-(c1-c6alkyl) or c1-c6an alkyl group;r8each independently is h or c1-c6an alkyl group;r9each independently is c1-c6alkyl radical, c2-c6alkenyl radical, c3-c12cycloalkyl radical, c3-c12heterocyclic group, c1-c12heteroaryl group, c6-c20an aryl group; - (c)1-c6alkyl diyl) - (c)3-c12cycloalkyl), - (c)1-c6alkyl diyl) - (c)3-c12heterocyclyl), - (c)1-c6alkyl diyl) - (c)1-c6heteroaryl), - (c)1-c6alkyl diyl) - (c)6-c20aryl) or- (c)1-c6alkyl diyl) -o- (c6-c20aryl groups); and iswherein the cycloalkyl, heterocyclyl, heteroaryl, aryl, alkyl, alkyldiyl, and alkenyl are optionally and independently substituted with one or more substituents selected from the group consisting of: f. cl, br, i, -cn, -ch3、-ch2ch3、-ch2ch2ch3、-ch(ch3)2、-ch2ch(ch3)2、-ch(ch3)ch2ch3、-ch2c(ch3)3、-ch2oh、-ch2och3、-ch2ch2oh、-c(ch3)2oh、-ch(oh)ch(ch3)2、-c(ch3)2ch2oh、-ch2ch2ch2oh、-ch2ch2c(ch3)2oh、-ch2ch2och3、-ch2ch(ch3)och3、-ch2ch2ch2och3、-ch2ch2c(ch3)2och3、-ch2ch2so2ch3、-ch2op(o)(oh)2、-ch2f、-chf2、-ch2nh2、-ch2nhso2ch3、-ch2nhch3、-ch2n(ch3)2、-cf3、-ch2cf3、-ch2chf2、-ch2ch2chf2、-ch2ch2cf3、-ch(ch3)cn、-c(ch3)2cn、-ch2cn、-co2h、-coch3、-co2ch3、-co2c(ch3)3、-coch(oh)ch3、-conh2、-conhch3、-conhch2ch3、-conhch(ch3)2、-con(ch3)2、-c(ch3)2conh2、-nh2、-nhch3、-n(ch3)2、-n(ch3)ch2ch3、-nhcoch3、-n(ch3)coch3、-nhs(o)2ch3、-n(ch3)c(ch3)2conh2、-n(ch3)ch2ch2s(o)2ch3、-no2、＝o、-oh、-och3、-och2ch3、-och2ch2och3、-och2ch2oh、-och2ch2n(ch3)2、-op(o)(oh)2、-s(o)2n(ch3)2、-sch3、-s(o)2ch3、-s(o)3h. cyclopropyl, cyclopropylamide, cyclobutyl, oxetanyl, azetidinyl, 1-methylazetidin-3-yl) oxy, n-methyl-n-oxetan-3-ylamino, azetidin-1-ylmethyl, benzyloxyphenyl, pyrrolidin-1-yl-methanone, phenyl, piperazin-1-yl, piperidin-1-yl, morpholinomethyl, morpholino-methanone and morpholino.
피리미딘일-피리딜옥시-나프틸 화합물 및 IRE1-관련 질환 및 장애 치료 방법본 명세서에는 본 명세서에 기재된 치환체 및 구조 특징을 갖고, 하기 화학식 (I) 또는 (I') 구조를 갖는, 이노시톨 요구 효소 1(IRE1) 조절 활성도 또는 기능을 가진 피리미딘일-피리딜옥시-나프틸 화합물, 또는 이의 입체이성질체, 호변이성질체 또는 약제학적으로 허용 가능한 염이 기재된다:[이미지]. 또한 화학식 (I) 또는 (I') 화합물을 포함하는 약제학적 조성물 및 의약뿐만 아니라, 에스트로겐 수용체에 의존하거나 매개되는 질환 또는 병태를 치료하기 위하여, 이러한 IRE1 조절제를 단독으로 또는 다른 치료제와 병용하여 사용하는 방법이 기재된다.하기 화학식 I'의 화합물, 또는 이의 입체이성질체, 호변이성질체 또는 약제학적으로 허용 가능한 염:[이미지]식 중,R1은 C3-C12 사이클로알킬, C3-C12 헤테로사이클릴, C1-C12 헤테로아릴, C6-C20 아릴, -(C1-C6 알킬다이일)-(C3-C12 사이클로알킬), 또는 -(C1-C6 알킬다이일)-(C3-C12 헤테로사이클릴)이고;R2는 H, F, Cl, -CN, -OCH3, -OCH2CH3 또는 C1-C6 알킬이고;R3은 H, -CN, C3-C12 사이클로알킬, C3-C12 헤테로사이클릴, C1-C12 헤테로아릴, C6-C20 아릴, -O-(C1-C12 헤테로아릴), -O-(C1-C6 알킬다이일)-(C6-C20 아릴), -N(R8)(C1-C6 알킬), -NR8C(O)R9, -NR8C(O)OR9, -NR8C(O)NHR9, -NR8SO2-(C1-C6 알킬), -NR8SO2-(C1-C6 알켄일), -NR8SO2-(C3-C12 사이클로알킬), -NR8SO2-(C1-C12 헤테로아릴), -NR8SO2-(C1-C6 알킬다이일)-(C3-C12 사이클로알킬), -NR8SO2-(C1-C6 알킬다이일)-(C3-C12 헤테로사이클릴), -NR8SO2-(C1-C6 알킬다이일)-(C1-C12 헤테로아릴), -NR8SO2-(C1-C6 알킬다이일)-(C6-C20 아릴), -NR8SO2NR8R9, 또는 -SO2NR8R9이고;R4는 H, -CN, C3-C12 사이클로알킬, C3-C12 헤테로사이클릴, C1-C12 헤테로아릴, C6-C20 아릴, -O-(C1-C12 헤테로아릴), -O-(C1-C6 알킬다이일)-(C6-C20 아릴), -NR8R9, -NR8C(O)R9, -NR8C(O)OR9, -NR8C(O)NHR9, -NR8SO2-(C1-C6 알킬), -NR8SO2-(C1-C6 알켄일), -NR8SO2-(C1-C12 헤테로아릴), -NR8SO2-(C3-C12 사이클로알킬), -NR8SO2-(C3-C12 헤테로사이클릴), -NR8SO2-(C1-C6 알킬다이일)-(C3-C12 사이클로알킬), -NR8SO2-(C1-C6 알킬다이일)-(C3-C12 헤테로사이클릴), -NR8SO2-(C1-C6 알킬다이일)-(C1-C12 헤테로아릴), -NR8SO2-(C1-C6 알킬다이일)-(C6-C20 아릴), -NR8SO2NR8R9, 또는 -SO2NR8R9이고;각각의 R5 및 R7은 독립적으로 H, F, Cl, -CN, -CH2OH, -C(O)NH2, -OH, -OCH3, -OCH2CH3 또는 C1-C6 알킬이고;n은 0, 1, 2 또는 3이고;각각의 R6은 독립적으로 H, F, Cl, Br, I, -CN, -NO2, -O-(C1-C6 알킬) 또는 C1-C6 알킬이고;각각의 R8은 독립적으로 H, 또는 C1-C6 알킬이고;각각의 R9는 독립적으로 C1-C6 알킬, C2-C6 알켄일, C3-C12 사이클로알킬, C3-C12 헤테로사이클릴, C1-C12 헤테로아릴, C6-C20 아릴; -(C1-C6 알킬다이일)-(C3-C12 사이클로알킬), -(C1-C6 알킬다이일)-(C3-C12 헤테로사이클릴), -(C1-C6 알킬다이일)-(C1-C6 헤테로아릴), -(C1-C6 알킬다이일)-(C6-C20 아릴), 또는 -(C1-C6 알킬다이일)-O-(C6-C20 아릴)이고; 그리고사이클로알킬, 헤테로사이클릴, 헤테로아릴, 아릴, 알킬, 알킬다이일 및 알켄일은 F, Cl, Br, I, -CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -CH2C(CH3)3, -CH2OH, -CH2OCH3, -CH2CH2OH, -C(CH3)2OH, -CH(OH)CH(CH3)2, -C(CH3)2CH2OH, -CH2CH2CH2OH, -CH2CH2C(CH3)2OH, -CH2CH2OCH3, -CH2CH(CH3)OCH3, -CH2CH2CH2OCH3, -CH2CH2C(CH3)2OCH3, -CH2CH2SO2CH3, -CH2OP(O)(OH)2, -CH2F, -CHF2, -CH2NH2, -CH2NHSO2CH3, -CH2NHCH3, -CH2N(CH3)2, -CF3, -CH2CF3, -CH2CHF2, -CH2CH2CHF2, -CH2CH2CF3, -CH(CH3)CN, -C(CH3)2CN, -CH2CN, -CO2H, -COCH3, -CO2CH3, -CO2C(CH3)3, -COCH(OH)CH3, -CONH2, -CONHCH3, -CONHCH2CH3, -CONHCH(CH3)2, -CON(CH3)2, -C(CH3)2CONH2, -NH2, -NHCH3, -N(CH3)2, -N(CH3)CH2CH3, -NHCOCH3, -N(CH3)COCH3, -NHS(O)2CH3, -N(CH3)C(CH3)2CONH2, -N(CH3)CH2CH2S(O)2CH3, -NO2, =O, -OH, -OCH3, -OCH2CH3, -OCH2CH2OCH3, -OCH2CH2OH, -OCH2CH2N(CH3)2, -OP(O)(OH)2, -S(O)2N(CH3)2, -SCH3, -S(O)2CH3, -S(O)3H, 사이클로프로필, 사이클로프로필아마이드, 사이클로부틸, 옥세탄일, 아제티딘일, 1-메틸아제티딘-3-일)옥시, N-메틸-N-옥세탄-3-일아미노, 아제티딘-1-일메틸, 벤질옥시페닐, 피롤리딘-1-일, 피롤리딘-1-일-메탄온, 페닐, 피페라진-1-일, 피페리딘-1-일, 몰폴리노메틸, 몰폴리노-메탄온 및 몰폴리노로 이루어진 군으로부터 선택된 1개 이상의 치환체로 선택적으로 그리고 독립적으로 치환된다.