INHIBITORS OF MENIN-MLL INTERACTIONThe present invention relates to the inhibitor of Multiple Endocrine tumor albumen (menin) and the interaction of MLL and MLL fusion proteins, contain its pharmaceutical composition and their purposes in treating cancer and the Other diseases mediated by Multiple Endocrine tumor albumen-MLL interaction.Compound of formula i：or its pharmaceutically acceptable salt, wherein：a, b, c and d are each independently selected from-c (ra1)(ra2)-,-c (ra1)(ra2)-c(ra1)(ra2)-,-c (=o)-and-c (ra1)(ra2)-c (=o)-, no more than one is-c (r wherein in a, b, c and da1)(ra2)-c (=o)-or-c (=o)-；l is selected from-c1-6alkylidene-and-(c1-4alkylidene)a-y-(c1-4alkylidene)b, wherein the c1-6alkylidene and described- (c1-4alkylidene)a-y-(c1-4alkylidene)barbitrary c in group1-4alkylidene is optionally replaced by 1,2 or 3 substituent group, described substituent group is independently selected from halogenated, cn, oh, c1-3alkyl, c1-3alkoxy, c1-3halogenated alkyl, c1-3halogenated alkoxy, amino, c1-3alkyl amino and two (c1-3alkyl) amino；y is independently selected from-o- ,-s- ,-s (=o)-,-s (=o)2,-c (=o)-,-c (=o) nry,-c (=o) o- ,-oc (=o) nry,-nry,-nryc (=o) o- ,-nryc (=o) nry,-s (=o)2nry,-c (=nrz)-, and-c (=nrz)- nry, wherein each ryindependently selected from h or c1-6alkyl, and wherein each rzindependently selected from h, c1-6alkyl and cn；cy is c6-14aryl, c3-18naphthenic base, 5-16 unit's heteroaryls or 4-18 membered heterocycloalkyls, respectively optionally by 1,2,3 or 4 a substituent group substitution, the substituent group is independently selected from rcy；each rcyindependently selected from halogenated, c1-6alkyl, c1-4halogenated alkyl, c1-4cyanoalkyl, c2-6alkenyl, c2-6alkynyl, c6-10virtue base, c3-10naphthenic base, 5-10 unit's heteroaryls, 4-10 membered heterocycloalkyls, cn, no2, ora1, sra1, c (o) rb1, c (o) nrc1rd1, c (o)ora1, oc (o) rb1, oc (o) nrc1rd1, c (=nre1)nrc1rd1, nrc1c (=nre1)nrc1rd1, nrc1rd1, nrc1c(o) rb1, nrc1c(o)ora1, nrc1c(o)nrc1rd1, nrc1s(o)rb1, nrc1s(o)2rb1, nrc1s(o)2nrc1rd1, s (o) rb1, s (o) nrc1rd1, s (o)2rb1and s (o)2nrc1rd1, wherein the c1-6alkyl, c2-6alkenyl, c2-6alkynyl, c6-10aryl, c3-10cycloalkanes base, 5-10 unit's heteroaryls and 4-10 membered heterocycloalkyls are respectively optionally replaced by 1,2,3 or 4 substituent group, and the substituent group is independent ground is selected from cn, no2, ora1, sra1, c (o) rb1, c (o) nrc1rd1, c (o) ora1, oc (o) rb1, oc (o) nrc1rd1, c (=nre1) nrc1rd1, nrc1c (=nre1)nrc1rd1, nrc1rd1, nrc1c(o)rb1, nrc1c(o)ora1, nrc1c(o)nrc1rd1, nrc1s(o) rb1, nrc1s(o)2rb1, nrc1s(o)2nrc1rd1, s (o) rb1, s (o) nrc1rd1, s (o)2rb1and s (o)2nrc1rd1；r1it is h, cy1, halogenated, c1-6alkyl, c1-4halogenated alkyl, c1-4cyanoalkyl, c2-6alkenyl, c2-6alkynyl, cn, no2, ora2, sra2, c (o) rb2, c (o) nrc2rd2, c (o) ora2, oc (o) rb2, oc (o) nrc2rd2, c (=nre2)nrc2rd2, nrc2c (=nre2) nrc2rd2, nrc2rd2, nrc2c(o)rb2, nrc2c(o)ora2, nrc2c(o)nrc2rd2, nrc2s(o)rb2, nrc2s(o)2rb2, nrc2s (o)2nrc2rd2, s (o) rb2, s (o) nrc2rd2, s (o)2rb2with s (o)2nrc2rd2, wherein the c1-6alkyl, c2-6alkenyl and c2-6 alkynyl is respectively optionally replaced by 1,2,3 or 4 substituent group, and the substituent group is independently selected from cn, no2, ora2, sra2, c (o) rb2, c (o) nrc2rd2, c (o) ora2, oc (o) rb2, oc (o) nrc2rd2, c (=nre2)nrc2rd2, nrc2c (=nre2)nrc2rd2, nrc2rd2, nrc2c(o)rb2, nrc2c(o)ora2, nrc2c(o)nrc2rd2, nrc2s(o)rb2, nrc2s(o)2rb2, nrc2s(o)2nrc2rd2, s (o) rb2, s (o) nrc2rd2, s (o)2rb2and s (o)2nrc2rd2；z is formula (z-1) or the group of (z-2)：x1selected from cr7and n；x2selected from s, cr8and n；x3selected from ch, s, o and nrn；x4selected from cr9and n；represent singly-bound or double bond, wherein one in formula (z-1) groupit is double bond and the other is singly-bound；each r2, r3, r4, r5, r6, r7, r8and r9it is halogenated independently selected from h, c1-6alkyl, c1-4halogenated alkyl, c1-4cyanoalkyl, c2-6alkenyl, c2-6alkynyl, cn, no2, ora3, sra3, c (o) rb3, c (o) nrc3rd3, c (o) ora3, oc (o) rb3, oc (o) nrc3rd3, c (=nre3)nrc3rd3, nrc3c (=nre3)nrc3rd3, nrc3rd3, nrc3c(o)rb3, nrc3c(o)ora3, nrc3c(o) nrc3rd3, nrc3s(o)rb3, nrc3s(o)2rb3, nrc3s(o)2nrc3rd3, s (o) rb3, s (o) nrc3rd3, s (o)2rb3and s (o)2nrc3rd3, wherein the c1-6alkyl, c2-6alkenyl and c2-6alkynyl is respectively optionally replaced by 1,2,3 or 4 substituent group, described to take dai ji is independently selected from cn, no2, ora3, sra3, c (o) rb3, c (o) nrc3rd3, c (o) ora3, oc (o) rb3, oc (o) nrc3rd3, c (=nre3)nrc3rd3, nrc3c (=nre3)nrc3rd3, nrc3rd3, nrc3c(o)rb3, nrc3c(o)ora3, nrc3c(o)nrc3rd3, nrc3s(o)rb3, nrc3s(o)2rb3, nrc3s(o)2nrc3rd3, s (o) rb3, s (o) nrc3rd3, s (o)2rb3and s (o)2nrc3rd3；rnit is h or c1-6alkyl is optionally replaced by 1,2,3 or 4 substituent group, and the substituent group is independently selected from cn, no2, ora3, sra3, c (o) rb3, c (o) nrc3rd3, c (o) ora3, oc (o) rb3, oc (o) nrc3rd3, c (=nre3)nrc3rd3, nrc3c (= nre3)nrc3rd3, nrc3rd3, nrc3c(o)rb3, nrc3c(o)ora3, nrc3c(o)nrc3rd3, nrc3s(o)rb3, nrc3s(o)2rb3, nrc3s(o)2nrc3rd3, s (o) rb3, s (o) nrc3rd3, s (o)2rb3and s (o)2nrc3rd3；a1it is halogenated selected from h, c1-6alkyl, c1-4halogenated alkyl, c1-4halogenated alkoxy, c1-4cyanoalkyl, c2-6alkenyl, c2-6alkynes base, c6-10aryl, c3-10naphthenic base, 5-10 unit's heteroaryls, 4-10 membered heterocycloalkyls, cn, no2, ora4, sra4, c...
메닌-MLL 상호작용의 억제제본 발명은 메닌과 MLL 및 MLL 융합 단백질의 상호작용의 억제제, 이를 함유하는 약학 조성물, 및 메닌-MLL 상호작용에 의해 매개되는 암 및 다른 질환의 치료에서의 이의 용도에 관한 것이다. 하기 화학식 I의 화합물 또는 이의 약학적으로 허용되는 염:[이미지]상기 식에서, A, B, C 및 D는 -C(RA1)(RA2)-, -C(RA1)(RA2)-C(RA1)(RA2)-, -C(=O)- 및 -C(RA1)(RA2)-C(=O)-로부터 각각 독립적으로 선택되고, 여기서 A, B, C 및 D 중 하나 이하는 -C(RA1)(RA2)-C(=O)- 또는 -C(=O)-이고;L은 -C1-6 알킬렌- 및 -(C1-4 알킬렌)a-Y-(C1-4 알킬렌)b-로부터 선택되고, 여기서 C1-6 알킬렌기 및 -(C1-4 알킬렌)a-Y-(C1-4 알킬렌)b-기의 임의의 C1-4 알킬렌기는 할로, CN, OH, C1-3 알킬, C1-3 알콕시, C1-3 할로알킬, C1-3 할로알콕시, 아미노, C1-3 알킬아미노 및 디(C1-3 알킬)아미노로부터 독립적으로 선택된 1, 2 또는 3 개의 치환기로 임의로 치환되고; Y는 -O-, -S-, -S(=O)-, -S(=O)2-, -C(=O)-, -C(=O)NRy-, -C(=O)O-, -OC(=O)NRy-, -NRy-, -NRyC(=O)O-, -NRyC(=O)NRy-, -S(=O)2NRy-, -C(=NRz)- 및 -C(=NRz)-NRy-로부터 독립적으로 선택되고, 여기서 각각의 Ry는 H 또는 C1-6 알킬로부터 독립적으로 선택되고, 각각의 Rz는 H, C1-6 알킬 및 CN으로부터 독립적으로 선택되고;Cy는 C6-14 아릴, C3-18 사이클로알킬, 5-16원의 헤테로아릴 또는 4-18원의 헤테로사이클로알킬이고, 이들 각각은 RCy로부터 독립적으로 선택된 1, 2, 3 또는 4 개의 치환기로 임의로 치환되고;각각의 RCy는 할로, C1-6 알킬, C1-4 할로알킬, C1-4 시아노알킬, C2-6 알케닐, C2-6 알키닐, C6-10 아릴, C3-10 사이클로알킬, 5-10원의 헤테로아릴, 4-10원의 헤테로사이클로알킬, CN, NO2, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, C(=NRe1)NRc1Rd1, NRc1C(=NRe1)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1 및 S(O)2NRc1Rd1로부터 독립적으로 선택되고, 여기서 상기 C1-6 알킬, C2-6 알케닐, C2-6 알키닐, C6-10 아릴, C3-10 사이클로알킬, 5-10원의 헤테로아릴 및 4-10원의 헤테로사이클로알킬은 CN, NO2, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, C(=NRe1)NRc1Rd1, NRc1C(=NRe1)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1 및 S(O)2NRc1Rd1로부터 독립적으로 선택된 1, 2, 3 또는 4 개의 치환기로 각각 임의로 치환되고;R1은 H, Cy1, 할로, C1-6 알킬, C1-4 할로알킬, C1-4 시아노알킬, C2-6 알케닐, C2-6 알키닐, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2 및 S(O)2NRc2Rd2이고, 여기서 상기 C1-6 알킬, C2-6 알케닐 및 C2-6 알키닐은 CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2 및 S(O)2NRc2Rd2로부터 독립적으로 선택된 1, 2, 3 또는 4 개의 치환기로 각각 임의로 치환되고;Z는 하기 화학식 (Z-1) 또는 (Z-2)의 기이고:[이미지]X1은 CR7 및 N으로부터 선택되고;X2는 S, CR8 및 N으로부터 선택되고;X3은 CH, S, O 및 NRN으로부터 선택되고;X4는 CR9 및 N으로부터 선택되고;[이미지]은 단일 또는 이중 결합을 나타내고, 화학식 (Z-1)의 기에서 하나의 [이미지]은 이중 결합이고 다른 하나는 단일 결합이고;각각의 R2, R3, R4, R5, R6, R7, R8 및 R9는 H, 할로, C1-6 알킬, C1-4 할로알킬, C1-4 시아노알킬, C2-6 알케닐, C2-6 알키닐, CN, NO2, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, NRc3S(O)Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3 및 S(O)2NRc3Rd3으로부터 독립적으로 선택되고, 여기서 상기 C1-6 알킬, C2-6 알케닐 및 C2-6 알키닐은 CN, NO2, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, NRc3S(O)Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3 및 S(O)2NRc3Rd3으로부터 독립적으로 선택된 1, 2, 3 또는 4 개의 치환기로 각각 임의로 치환되고;RN은 H이거나, CN, NO2, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, NRc3S(O)Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3 및 S(O)2NRc3Rd3으로부터 독립적으로 선택된 1, 2, 3 또는 4 개의 치환기로 임의로 치환된 C1-6 알킬이고;A1은 H, 할로, C1-6 알킬, C1-4 할로알킬, C1-4 할로알콕시, C1-4 시아노알킬, C2-6 알케닐, C2-6 알키닐, C6-10 아릴, C3-10 사이클로알킬, 5-10원의 헤테로아릴, 4-10원의 헤테로사이클로알킬, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, C(=NRe4)NRc4Rd4, NRc4C(=NRe4)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4 및 S(O)2NRc4Rd4로부터 선택되고, 여기서 상기 C1-6 알킬, C2-6 알케닐, C2-6 알키닐, C6-10 아릴, C3-10 사이클로알킬, 5-10원의 헤테로아릴 및 4-10원의 헤테로사이클로알킬은 CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, C(=NRe4)NRc4Rd4, NRc4C(=NRe4)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4 및 S(O)2NRc4Rd4로부터 독립적으로 선택된 1, 2, 3 또는 4 개의 치환기로 각각 임의로 치환되고;A2는 H, 할로, C1-6 알킬, C1-4 할로알킬, C1-4 할로알콕시, C1-4 시아노알킬, C2-6 알케닐, C2-6 알키닐, C6-10 아릴, C3-10 사이클로알킬, 5-10원의 헤테로아릴, 4-10원의 헤테로사이클로알킬, CN, NO2, ORa5, SRa5, C(O)Rb5, C(O)NRc5Rd5, C(O)ORa5, OC(O)Rb5, OC(O)NRc5Rd5, C(=NRe5)NRc5Rd5, NRc5C(=NRe5)NRc5Rd5, NRc5Rd5, NRc5C(O)Rb5, NRc5C(O)ORa5, NRc5C(O)NRc5Rd5, NRc5S(O)Rb5, NRc5S(O)2Rb5, NRc5S(O)2NRc5Rd5, S(O)Rb5, S(O)NRc5Rd5, S(O)2Rb5 및 S(O)2NRc5Rd5로부터 선택되고, 여기서 상기 C1-6 알킬, C2-6 알케닐, C2-6 알키닐, C6-10 아릴, C3-10 사이클로알킬, 5-10원의 헤테로아릴 및 4-10원의 헤테로사이클로알킬은 CN, NO2, ORa5, SRa5, C(O)Rb5, C(O)NRc5Rd5, C(O)ORa5, OC(O)Rb5, OC(O)NRc5Rd5, C(=NRe5)NRc5Rd5, NRc5C(=NRe5)NRc5Rd5, NRc5Rd5, NRc5C(O)Rb5, NRc5C(O)ORa5, NRc5C(O)NRc5Rd5, NRc5S(O)Rb5, NRc5S(O)2Rb5, N...