SPIRO-CONDENSED PYRROLIDINE DERIVATIVES AS DEUBIQUITYLATING ENZYMES (DUB) INHIBITORSThe present invention relates to novel compounds and methods for the manufacture of inhibitors of deubiquitylating enzymes (DUBs). In particular, the invention relates to the inhibition of Cezanne 1. The invention further relates to the use of DUB inhibitors in the treatment of cancer. (Figure (I))A compound of formula I:(I)or a pharmaceutically acceptable salt thereof, wherein:Rla, Rlb, Rlc and Rld each independently represent hydrogen or an optionally substituted Ci-C6 alkyl, or Rla and Rlb together form an optionally substituted cycloalkyl ring, Rlc and Rld together form an optionally substituted cycloalkyl ring, or Rld together with Rle forms an optionally substituted cycloalkyl ring;Rle and Rlf each independently represent hydrogen, fluorine, cyano, hydroxyl, amino, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 alkoxy or an optionally substituted 5 or 6 membered heteroaryl or aryl ring, or Rle forms an optionally substituted cycloalkyl ring with Rlf or Rld;ring A is a 5 to 11 membered monocyclic or bicyclic heterocyclyl ring which may be optionally further substituted.The compound according to claim 1, wherein ring A is further substituted with one or more - (^-(R2),! moiety, wherein each -(^-(R2),! is the same or different and wherein:n is 0 or 1;Q1 represents halogen, cyano, oxo, nitro, hydroxyl, -SR3, -NR R4, -CONR R4, -NR COR4, - NR CONR4R4a, -COR3, -C(0)OR3, -S02R3, -S02NR R4, -NR S02R4, NR S02NR4R4a, - NR C(0)OR4, optionally substituted -Ci-C6 alkyl, optionally substituted -Ci-C6 alkoxy, optionally substituted -C2-C6 alkenyl, optionally substituted -C2-C6 alkynyl, a covalent bond, an oxygen atom, a sulphur atom, -OR5-, -SO-, -S02-, -CO-, -C(0)0-, -C0-C3 alkylene- CONR -Co-C3 alkylene, -C0-C3 alkylene-NR -C0-C3 alkylene, -C0-C3 alkylene-NR CO-C0-C3 alkylene, -C0-C3 alkylene-NR CONR4-C0-C3 alkylene, -S02NR3-, -NR S02-, -NR S02NR4-, - NR C(0)0-, -NR C(0)OR5-, optionally substituted Ci-C6 alkylene or optionally substituted - C2-C<5 alkenylene;R2 represents an optionally substituted 3 to 10 membered ring, wherein the optional substituents are selected from halogen, cyano, oxo, nitro, hydroxyl -SR6, -NR6R7, -CONR6R7, -NR6COR7, -NR6CONR R7a, -COR6, -C(0)OR6, -S02R6, -S02NR6R7, -NR6S02R7, NR6S02NR7R7a, -NR6C(0)OR7, -d-C6 alkyl, -d-C6 alkoxy ,-C2-C6 alkenyl, -C2-C6, -Q2a-R8, -Q2b-NR6CONR R7a, -Q2b-NR6CONR7-Q2c-R8, -Q2b-NR6R7, -Q2b-NR6-Q2c-R8, -Q2b-COR6, - Q2b-CO-Q2c-R8, -Q2b-NR6COR7, -Q2b-NR6CO-Q2c-R8, -Q2b-NR6C(0)OR7, -Q2b-NR6C(0)0- Q2 _r8 _Q2b.SQ2R6 .Q2b.So2-Q2C-R8, -Q2b-CONR6R7, -Q2b-CONR6-Q2c-R8, -Q2b-C02R6, -Q2B- C02-Q2c-R8, -Q2b-S02NR6R7, -Q2b-S02NR6-Q2c-R8, -Q2-NR6S02R7, -Q2-NR6S02-Q2c-R8, - Q2b-NR6S02NR R7a and -Q2b-NR6S02NR7-Q2c-R8, wherein the alkyl, alkoxy, alkenyl or alkynyl are optionally substituted with one or more substituents selected from halogen, hydroxyl, thiol, cyano, amino, nitro and SF5, whereinQ2a represents a covalent bond, an oxygen atom, a sulphur atom, -SO-, -S02-, -CO-, optionally substituted Ci-C6 alkylene or optionally substituted C2-C6 alkenylene;Q2b and Q2c each independently represent a covalent bond, optionally substituted Ci-C6 alkylene or optionally substituted C2-C6 alkylenylene;R6, R7 and R7a each independently represent hydrogen or optionally substituted Ci-C6 alkyl; andR8 represents optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, or an optionally substituted cycloalkyl;R3, R4 and R4a each independently represent hydrogen or optionally substituted Ci-C6 alkyl; andR5 represents optionally substituted Ci-C6 alkylene.The compound according to any preceding claim, wherein ring A contains 1 to 4 heteroatoms.The compound according to any preceding claim, wherein ring A is a bicyclic ring.The compound according to any one of claims 1 to 3, wherein ring A is a monocyclic ring.The compound according to any one of claims 1 to 2, wherein ring A is selected from piperidin-2-one, indoline-2-one, piperazine-2-one, pyrrolidin-2-one, 3,4-dihydroquinolin- 2( lH)-one, lH-pyrido [2,3 -b] [ 1 ,4]oxazin-2(3H)-one, 3 ,4-dihydropyrido [2,3 -6]pyrazine-2( 1H)- one, 1 ,5 -diydrobenzo [e] [ 1 ,4] oxazepin-2(3H)-one, 3 ,4-dihydro- 1 ,5 -naphthyridin-2( lH)-one, 3 ,4-dihydro- 1 ,6-naphthyridin-2( lH)-one, 3 ,4-dihydro- 1 ,7-naphthyridin-2( lH)-one, 3,4- dihydro-l,8-naphthyridin-2(lH)-one and 3,4-dihydropyrazino[2,3-6]pyrazine-2(lH)-one and 1 ,2,3 ,5 -tetrahydro-4H-pyrido [2,3 -b] [ 1 ,4]diazepin-4-one .The compound according to claim 6, wherein ring A is selected from pyrrolidin-2-one, piperazine2-one, 3,4-dihydroquinolin-2(lH)-one, lH-pyrido[2,3-6][l,4]oxazin-2(3H)-one, 3 ,4-dihydropyrido [2,3 -6]pyrazine-2( lH)-one, 1 ,5 -dihydrobenzo [e] [ 1 ,4]oxazepin-2(3H)-one and 1,2,3,5 -tetrahydro-4H-pyrido [2, 3 -b] [ 1 ,4] diazepin-4 -one .The compound according to any one of claims 2 to 7, wherein ring A is either not further su ibbssttiittuuted or is further substituted with one, two or three -(^-(R2),! moieties , wherein each(^-(R2),! moiety is the same or different.The compound according to any one of claims 2 to 8, wherein R2 is selected from piperidiniyl, pyrrolyl, phenyl, pyrazolyl, isoxazolyl, indazolyl, pyridinyl, dihidropyridinyl, benzothiazolyl and pyrimidinyl.The compound according to any preceding claim, w...
탈유비퀴틴화 효소(DUB) 억제제로서 스피로-축합된 피롤리딘 유도체본 발명은 탈유비퀴틴화 효소(DUB)의 억제제의 제조 방법을 위한 신규한 화합물 및 방법에 관한 것이다. 특히, 본 발명은 세잔 1의 억제에 관한 것이다. 본 발명은 또한 암의 치료에서 DUB 억제제의 용도에 관한 것이다.하기 화학식 I의 화합물 또는 이의 약학적으로 허용되는 염:[화학식 I]상기 식에서,R1a, R1b, R1c 및 R1d는 각각 독립적으로 수소 또는 임의적으로 치환된 C1-C6 알킬이거나, R1a 및 R1b는 함께 임의적으로 치환된 사이클로알킬 고리를 형성하거나, R1c 및 R1d는 함께 임의적으로 치환된 사이클로알킬 고리를 형성하거나, R1d는 R1e와 함께 임의적으로 치환된 사이클로알킬 고리를 형성하고;R1e 및 R1f는 각각 독립적으로 수소, 불소, 시아노, 하이드록실, 아미노, 임의적으로 치환된 C1-C6 알킬, 임의적으로 치환된 C1-C6 알콕시 또는 임의적으로 치환된 5 또는 6원 헤테로아릴 또는 아릴 고리이거나, R1e는 R1f 또는 R1d와 함께 임의적으로 치환된 사이클로알킬 고리를 형성하고;고리 A는 임의적으로 추가로 치환될 수 있는 5 내지 11원 단환형 또는 이환형 헤테로사이클릴 고리이다.