PYRIDAZINONES AS PARP7 INHIBITORSThe present invention relates to pyridazinones and related compounds of Formula I which are inhibitors of PARP7 and are useful in the treatment of cancer.A compound of formula i:or a pharmaceutically acceptable salt thereof, wherein:x is cl, br, ch3、cf3、cn、och3ethyl, cyclopropyl, sch3or an isopropyl group;a is a group having a formula selected from (a-1), (a-2) and (a-3):y1、y2and y3each independently selected from o, s, nry、c(＝o)、c(＝o)o、c(＝o)nry、s(＝o)、s(＝o)2、s(＝o)nry、s(＝o)2nryor nryc(＝o)nrywherein each r isyindependently is h orc1-4an alkyl group;l is c1-3alkylene group, o, s, nry、c(＝o)、c(＝o)o、c(＝o)nry、s(＝o)、s(＝o)nryor nryc(＝o)nry；z is h, cyzhalogen radical, c1-6alkyl radical, c2-6alkenyl radical, c2-6alkynyl, c1-6haloalkyl, cn, no2、ora、sra、c(o)rb、c(o)nrcrd、c(o)ora、oc(o)rb、oc(o)nrcrd、nrcrd、nrcc(o)rb、nrcc(o)ora、nrcc(o)nrcrd、c(＝nre)rb、c(＝nre)nrcrd、nrcc(＝nre)nrcrd、nrcs(o)rb、nrcs(o)2rb、nrcs(o)2nrcrd、s(o)rb、s(o)nrcrd、s(o)2rband s (o)2nrcrd(ii) a wherein said c of z1-6alkyl radical, c2-6alkenyl radical, c2-6alkynyl and c1-6haloalkyl is each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from: cy is a cy-zhalogen, cn, no 2、ora、sra、c(o)rb、c(o)nrcrd、c(o)ora、oc(o)rb、oc(o)nrcrd、c(＝nre)nrcrd、nrcc(＝nre)nrcrd、nrcrd、nrcc(o)rb、nrcc(o)ora、nrcc(o)nrcrd、nrcs(o)rb、nrcs(o)2rb、nrcs(o)2nrcrd、s(o)rb、s(o)nrcrd、s(o)2rband s (o)2nrcrd；cyzis selected from c6-10aryl radical, c3-7cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from: halogen radical, c1-6alkyl radical, c2-6alkenyl radical, c2-6alkynyl, c1-6haloalkyl, 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)2nrc1rd1wherein said alkyl, c2-6alkenyl and c2-6alkynyl is optionally substituted with 1, 2 or 3 substituents independently selected from: halogen radical, 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；ring d is a monocyclic or polycyclic 4-10 membered heterocycloalkyl optionally substituted with 1, 2 or 3 groups independently selected from: halogen radical, c1-6alkyl radical, c2-6alkenyl radical, c2-6alkynyl, c1-6haloalkyl, 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)2nrc2rd2wherein said c is1-6alkyl radical, c2-6alkenyl and c2-6each alkynyl group is optionally substituted with 1, 2 or 3 groups independently selected from: halogen radical, 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；r1、r2、r3、r4、r5、r6、r7、r8、r9、r10、r11and r12each independently selected from h, halo, c1-6alkyl radical, c2-6alkenyl radical, c2-6alkynyl, c1-6haloalkyl, c6-10aryl radical, c3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, c6-10aryl-c1-4alkyl radical, c3-7cycloalkyl-c1-4alkyl, 5-10 membered heteroaryl-c1-4alkyl, 4-10 membered heterocycloalkyl-c1-4alkyl, cn, no2、ora3、sra3、c(o)rb3、c(o)nrc3rd3、c(o)ora3、oc(o)rb3、oc(o)nrc3rd3、nrc3rd3、nrc3c(o)rb3、nrc3c(o)ora3、nrc3c(o)nrc3rd3、c(＝nre3)rb3、c(＝nre3)nrc3rd3、nrc3c(＝nre3)nrc3rd3、nrc3s(o)rb3、nrc3s(o)2rb3、nrc3s(o)2nrc3rd3、s(o)rb3、s(o)nrc3rd3、s(o)2rb3and s (o)2nrc3rd3(ii) a wherein said r1、r2、r3、r4、r5、r6、r7、r8、r9、r10、r11and r12said c of1-6alkyl radical, c 2-6alkenyl radical, c2-6alkynyl, c1-6haloalkyl, c6-10aryl radical, c3-7cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, c6-10aryl-c1-4alkyl radical, c3-7cycloalkyl-c1-4alkyl, 5-10 membered heteroaryl-c1-4alkyl and 4-10 membered heterocycloalkyl-c1-4each alkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from: halogen radical, c1-6alkyl radical, c2-6alkenyl radical, c2-6alkynyl, c1-6haloalkyl, cn, no2、ora3、sra3、c(o)rb3、c(o)nrc3rd3、c(o)ora3、oc(o)rb3、oc(o)nrc3rd3、nrc3rd3、nrc3c(o)rb3、nrc3c(o)ora3、nrc3c(o)nrc3rd3、c(＝nre3)rb3、c(＝nre3)nrc3rd3、nrc3c(＝nre3)nrc3rd3、nrc3s(o)rb3、nrc3s(o)2rb3、nrc3s(o)2nrc3rd3、s(o)rb3、s(o)nrc3rd3、s(o)2rb3and s (o)2nrc3rd3；or r1and r3together with the carbon atom to which they are attached form c5-10a cycloalkyl ring or a 5-10 membered heterocycloalkyl ring, each of said rings optionally substituted with 1, 2 or 3 substituents independently selected from: halogen radical, c1-6alkyl radical, c2-6alkenyl radical, c2-6alkynyl, c1-6haloalkyl, cn, no2、ora3、sra3、c(o)rb3、c(o)nrc3rd3、c(o)ora3、oc(o)rb3、oc(o)nrc3rd3、nrc3rd3、nrc3c(o)rb3、nrc3c(o)ora3、nrc3c(o)nrc3rd3、c(＝nre3)rb3、c(＝nre3)nrc3rd3、nrc3c(＝nre3)nrc3rd3、nrc3s(o)rb3、nrc3s(o)2rb3、nrc3s(o)2nrc3rd3、s(o)rb3、s(o)nrc3...
PARP7 억제제로서의 피리다지논본 발명은 PARP7 억제제이고 암 치료에 유용한 화학식 I의 피리다지논 및 관련 화합물에 관한 것이다.[이미지]화학식 I의 화합물:[이미지]또는 그의 약제학적으로 허용 가능한 염으로서, 여기서:X는 Cl, Br, CH3, CF3, CN, OCH3, 에틸, 사이클로프로필, SCH3 또는 이소프로필이고;A는 (A-1), (A-2) 및 (A-3)으로부터 선택된 화학식을 갖는 기이고:[이미지][이미지]Y1, Y2, 및 Y3은 각각 O, S, NRY, C(=O), C(=O)O, C(=O)NRY, S(=O), S(=O)2, S(=O)NRY, S(=O)2NRY 또는 NRYC(=O)NRY로부터 독립적으로 선택되고, 여기서 각각의 RY는 독립적으로 H 또는 C1-4 알킬이고;L은 C1-3 알킬렌, O, S, NRY, C(=O), C(=O)O, C(=O)NRY, S(=O), S(=O)NRY, 또는 NRYC(=O)NRY이고;Z는 H, CyZ, 할로, C1-6 알킬, C2-6 알케닐, C2-6 알키닐, C1-6 할로알킬, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORa, NRcC(O)NRcRd, C(=NRe)Rb, C(=NRe)NRcRd, NRcC(=NRe)NRcRd, NRcS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, 및 S(O)2NRcRd이고; 여기서 Z의 상기 C1-6 알킬, C2-6 알케닐, C2-6 알키닐, 및 C1-6 할로알킬은 각각 CyZ, 할로, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, C(=NRe)NRcRd, NRcC(=NRe)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORa, NRcC(O)NRcRd, NRcS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, 및 S(O)2NRcRd로부터 독립적으로 선택된 1, 2, 3, 4, 또는 5개의 치환기로 임의로 치환되고;CyZ는 C6-10 아릴, C3-7 사이클로알킬, 5 내지 10원 헤테로아릴, 및 4 내지 10원 헤테로사이클로알킬로부터 선택되고, 각각은 할로, C1-6 알킬, C2-6 알케닐, C2-6 알키닐, C1-6 할로알킬, 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 4개의 치환기로 임의로 치환되고, 여기서 상기 알킬, C2-6 알케닐, 및 C2-6 알키닐은 할로, 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, 또는 3개의 치환기로 임의로 치환되고;고리 D는 할로, C1-6 알킬, C2-6 알케닐, C2-6 알키닐, C1-6 할로알킬, 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, 또는 3개의 기로 임의로 치환된 모노사이클릭 또는 폴리사이클릭 4 내지 10원 헤테로사이클로알킬 기이고, 여기서 상기 C1-6 알킬, C2-6 알케닐, 및 C2-6 알키닐은 각각 할로, 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, 또는 3개의 기로 임의로 치환되고;R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, 및 R12는 각각 H, 할로, C1-6 알킬, C2-6 알케닐, C2-6 알키닐, C1-6 할로알킬, C6-10 아릴, C3-7 사이클로알킬, 5 내지 10원 헤테로아릴, 4 내지 10원 헤테로사이클로알킬, C6-10 아릴-C1-4 알킬, C3-7 사이클로알킬-C1-4 알킬, 5 내지 10원 헤테로아릴-C1-4 알킬, 4 내지 10원 헤테로사이클로알킬-C1-4 알킬, CN, NO2, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, C(=NRe3)Rb3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, NRc3S(O)Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, 및 S(O)2NRc3Rd3로부터 독립적으로 선택되고; 여기서 상기 R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, 및 R12의 상기 C1-6 알킬, C2-6 알케닐, C2-6 알키닐, C1-6 할로알킬, C6-10 아릴, C3-7 사이클로알킬, 5 내지 10원 헤테로아릴, 4 내지 10원 헤테로사이클로알킬, C6-10 아릴-C1-4 알킬, C3-7 사이클로알킬-C1-4 알킬, 5 내지 10원 헤테로아릴-C1-4 알킬, 및 4 내지 10원 헤테로사이클로알킬-C1-4 알킬은 각각 할로, C1-6 알킬, C2-6 알케닐, C2-6 알키닐, C1-6 할로알킬, CN, NO2, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, C(=NRe3)Rb3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, NRc3S(O)Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, 및 S(O)2NRc3Rd3로부터 독립적으로 선택된 1, 2, 3, 4, 또는 5개의 치환기로 임의로 치환되거나;또는 R1 및 R3은 이들이 부착된 탄소 원자와 함께 C5-10 사이클로알킬 고리 또는 5 내지 10원 헤테로사이클로알킬 고리를 형성하고, 각각은 할로, C1-6 알킬, C2-6 알케닐, C2-6 알키닐, C1-6 할로알킬, CN, NO2, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, C(=NRe3)Rb3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, NRc3S(O)Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, 및 S(O)2NRc3Rd3로부터 독립적으로 선택된 1, 2, 또는 3개의 치환기로 임의로 치환되거나;또는 R3 및 R5는 이들이 부착된 탄소 원자와 함께 C5-10 사이클로알킬 고리 또는 5 내지 10원 헤테로사이클로알킬 고리를 형성하고, 각각은 할로, C1-6 알킬, C2-6 알케닐, C2-6 알키닐, C1-6 할로알킬, CN, NO2, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, C(=NRe3)Rb3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, NRc3S(O)Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, 및 S(O)2NRc3Rd3로부터 독립적으로 선택된 1, 2, 또는 3개의 치환기로 임의로 치환되거나;또는 R7 및 R9는 이들이 부착된 탄소 원자와 함께 C5-10 사이클로알킬 고리 또는 5 내지 10원 헤테로사이클로알킬 고리를 형성하고, 각각은 할로, C1-6 알킬, C2-6 알케닐, C2-6 알키닐, C1-6 할로알킬, CN, NO2, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, C(=NRe3)Rb3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, NRc3S(O)Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, 및 S(O)2NRc3Rd3로부터 독립적으로 선택된 1, 2, 또는 3개의 치환기로 임의로 치환되거나;또는 R9 ...