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EP-4735448-A1 - SUBSTITUTED SPIRO COMPOUND DERIVATIVES AND THEIR PHARMACEUTICAL USE

EP4735448A1EP 4735448 A1EP4735448 A1EP 4735448A1EP-4735448-A1

Abstract

Provided herein are novel spiro compound derivatives, compositions containing the compounds, and preparation methods and uses thereof. The spiro compound derivatives are compounds represented by Formula (I), or tautomers, stereoisomers, prodrugs, crystal forms, isotopically labeled forms, pharmaceutically acceptable salts, hydrates or solvates thereof. The compounds and compositions of the present disclosure can be used to treat diseases or disorders mediated by USP1, in particular, cancer.

Inventors

  • LEE, JUNG HUN
  • KHOO, JA HEOUK
  • CHOI, SOONGYU
  • PARK, YOUNG WHAN
  • AHN, JUNSEONG
  • JANG, Haeyeon
  • KIM, NA KYUNG

Assignees

  • Avelos Therapeutics Inc.

Dates

Publication Date
20260506
Application Date
20240626

Claims (20)

  1. A compound of the following Formula (I): (I) wherein: A is 5-12 membered heteroaryl or 5-12 membered heterocyclyl, wherein each of said heteroaryl and heterocyclyl is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C 2 -C 6 alkenyl, hydroxy, C 1 -C 6 alkoxy, amino, mercapto, oxo, 3-6 membered heterocyclyl, and R L1 , wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; L is selected from the group consisting of -(C 2 -C 6 alkynylene)-, -(6-14 membered arylene)-, -(7-11 membered polycyclic cycloalkylene)-, -(C 2 -C 6 alkynylene)-NH-, -(6-14 membered arylene)-NH-, and -(7-11 membered polycyclic cycloalkylene)-NH-, wherein said arylene is optionally substituted with one or more selected from C 1 -C 6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C 2 -C 6 alkenyl, hydroxy, C 1 -C 6 alkoxy, amino, mercapto, -(C 1 -C 6 alkylene)-N(C 1 -C 6 alkyl) 2 , and R L2 , wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; R L1 and R L2 , taken together with the atoms to which each R L1 and R L2 is attached, form a saturated or unsaturated 5-10 membered carbocyclic or heterocyclic group, wherein said carbocyclic or heterocyclic group is optionally substituted with one or more selected from C 1 -C 6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C 2 -C 6 alkenyl, hydroxy, C 1 -C 6 alkoxy, amino, and mercapto; q is an integer between 1 to 5; B is 5-12 membered heteroaryl, wherein said heteroaryl is optionally substituted with one or more selected from C 1 -C 6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C 2 -C 6 alkenyl, hydroxy, C 1 -C 6 alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; each of W 1 and W 2 is independently selected from N and CR 3 , wherein each of R 3 is independently selected from hydrogen, C 1 -C 6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, hydroxy, C 1 -C 6 alkoxy, amino, or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; each of X and Y is independently selected from the group consisting of a single bond, sulfur, oxygen, -N(R 1 )-, -C(O)-, and -CH(R 2 )-, wherein each of R 1 and R 2 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, hydroxy, halogen, and C 1 -C 6 alkoxy, wherein each of said alkyl and alkoxy is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; and each of n and m is independently an integer between 0 to 7, provided that when X and Y both are a single bond, m+n is greater than or equal to 2; and when either X or Y is a single bond, m+n is greater than or equal to 1, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof.
  2. The compound according to claim 1, wherein the compound is a compound represented by Formula (Ia): (Ia) wherein: A is 5-12 membered heteroaryl or 5-12 membered heterocyclyl, wherein each of said heteroaryl and heterocyclyl is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C 2 -C 6 alkenyl, hydroxy, C 1 -C 6 alkoxy, amino, mercapto, oxo, 3-6 membered heterocyclyl, and R L1 , wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; L is selected from the group consisting of -(C 2 -C 6 alkynylene)-, -(6-14 membered arylene)-, -(7-11 membered polycyclic cycloalkylene)-, -(C 2 -C 6 alkynylene)-NH-, -(6-14 membered arylene)-NH-, and -(7-11 membered polycyclic cycloalkylene)-NH-, wherein said arylene is optionally substituted with one or more selected from C 1 -C 6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C 2 -C 6 alkenyl, hydroxy, C 1 -C 6 alkoxy, amino, mercapto, -(C 1 -C 6 alkylene)-N(C 1 -C 6 alkyl) 2 , and R L2 , wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; R L1 and R L2 , taken together with the atoms to which each R L1 and R L2 is attached, form a saturated or unsaturated 5-10 membered carbocyclic or heterocyclic group, wherein said carbocyclic or heterocyclic group is optionally substituted with one or more selected from C 1 -C 6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C 2 -C 6 alkenyl, hydroxy, C 1 -C 6 alkoxy, amino, and mercapto; q is an integer between 1 to 5; B is 5-12 membered heteroaryl, wherein said heteroaryl is optionally substituted with one or more selected from C 1 -C 6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C 2 -C 6 alkenyl, hydroxy, C 1 -C 6 alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; each of W 1 and W 2 is independently selected from N and CR 3 , wherein each of R 3 is independently selected from hydrogen, C 1 -C 6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, hydroxy, C 1 -C 6 alkoxy, amino, or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; and n is an integer between 2 to 7.
  3. The compound according to any one of claims 1 to 2, wherein the compound is a compound represented by Formula (Ib): (Ib) wherein: A is 5-12 membered heteroaryl or 5-12 membered heterocyclyl, wherein each of said heteroaryl and heterocyclyl is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C 2 -C 6 alkenyl, hydroxy, C 1 -C 6 alkoxy, amino, mercapto, oxo, 3-6 membered heterocyclyl, and R L1 , wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; L is selected from the group consisting of -(C 2 -C 6 alkynylene)-, -(6-14 membered arylene)-, -(7-11 membered polycyclic cycloalkylene)-, -(C 2 -C 6 alkynylene)-NH-, -(6-14 membered arylene)-NH-, and -(7-11 membered polycyclic cycloalkylene)-NH-, wherein said arylene is optionally substituted with one or more selected from C 1 -C 6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C 2 -C 6 alkenyl, hydroxy, C 1 -C 6 alkoxy, amino, mercapto, -(C 1 -C 6 alkylene)-N(C 1 -C 6 alkyl) 2 , and R L2 , wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; R L1 and R L2 , taken together with the atoms to which each R L1 and R L2 is attached, form a saturated or unsaturated 5-10 membered carbocyclic or heterocyclic group, wherein said carbocyclic or heterocyclic group is optionally substituted with one or more selected from C 1 -C 6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C 2 -C 6 alkenyl, hydroxy, C 1 -C 6 alkoxy, amino, and mercapto; each of R b1 and R b3 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C 2 -C 6 alkenyl, hydroxy, C 1 -C 6 alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; W 1 is selected from N and CR 3 , wherein R 3 is selected from hydrogen, C 1 -C 6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, hydroxy, C 1 -C 6 alkoxy, amino, or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; W 3 is selected from N and CR 4 , wherein each of R 4 is selected from hydrogen, C 1 -C 6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C 2 -C 6 alkenyl, hydroxy, C 1 -C 6 alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; and n is an integer between 2 to 7.
  4. The compound according to any one of claims 1 to 3, wherein A is selected from the group consisting of: each of R a1 , R a2 , R a3 , R a4 , R a5 , R a6 , and R a7 is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, R L1 , ; wherein R aa is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoro, chloro, bromom, and iodo; L is selected from the group consisting of -phenylene-, , , and , wherein said phenylene is optionally substituted with one or more selected from methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, n-propoxy, isopropoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, -CH 2 N(CH 3 ) 2 , -CH 2 N(CH 2 CH 3 ) 2 , -CH 2 N(CH(CH 3 ) 2 ) 2 , and R L2 ; and R L1 and R L2 , taken together with the atoms to which each R L1 and R L2 is attached, form a saturated or unsaturated 6-9 membered heterocyclic group, wherein said heterocyclic group is optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, hydroxy, amino, and mercapto.
  5. The compound according to any one of claims 1 to 3, wherein the compound is a compound represented by Formula (Ic-1): (Ic-1) wherein: each of R a1 , R a2 , and R a3 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C 2 -C 6 alkenyl, hydroxy, C 1 -C 6 alkoxy, amino, mercapto, oxo, and 3-6 membered heterocyclyl, wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; each of R L21 , R L22 , R L23 , and R L24 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C 2 -C 6 alkenyl, hydroxy, C 1 -C 6 alkoxy, amino, mercapto, and -(C 1 -C 6 alkylene)-N(C 1 -C 6 alkyl) 2 , wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; each of R b1 and R b3 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C 2 -C 6 alkenyl, hydroxy, C 1 -C 6 alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; W 1 is selected from N and CR 3 , wherein R 3 is selected from hydrogen, C 1 -C 6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, hydroxy, C 1 -C 6 alkoxy, amino, or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; and W 3 is selected from N and CR 4 , wherein each of R 4 is selected from hydrogen, C 1 -C 6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C 2 -C 6 alkenyl, hydroxy, C 1 -C 6 alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; and n is an integer between 2 to 7.
  6. The compound according to any one of claims 1 to 3 and 5, wherein each of R a1 , R a2 , and R a3 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, oxo, and 3-5 membered heterocyclyl, wherein each of said alkyl and heterocyclyl is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, and halogen; each of R L21 , R L22 , R L23 , and R L24 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, and -(C 1 -C 6 alkylene)-N(C 1 -C 6 alkyl) 2 , wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, and halogen, each of R b1 and R b3 is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, and isopropoxy; W 1 is selected from N and CR 3 , wherein R 3 is selected from hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, fluoro, chloro, bromo, iodo, and trifluoromethyl; W 3 is selected from N and CR 4 , wherein each of R 4 is selected from hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, and isopropoxy; and n is an integer between 2 to 5.
  7. The compound according to any one of claims 1 to 3 and 5, wherein each of R a1 , R a2 , and R a3 is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, R aa is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoro, chloro, bromom, and iodo; each of R L21 , R L22 , R L23 , and R L24 is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, n-propoxy, isopropoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, -CH 2 N(CH 3 ) 2 , -CH 2 N(CH 2 CH 3 ) 2 , and -CH 2 N(CH(CH 3 ) 2 ) 2 ; each of R b1 and R b3 is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, and isopropoxy; W 1 is selected from N and CR 3 , wherein R 3 is selected from hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, fluoro, chloro, bromo, iodo, and trifluoromethyl; W 3 is selected from N and CR 4 , wherein each of R 4 is selected from hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, and isopropoxy; and n is an integer between 2 to 5.
  8. The compound according to any one of claims 1 to 3, wherein the compound is a compound represented by Formula (Ic-2): (Ic-2) wherein: each of R a2 , R a3 , and R a4 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C 2 -C 6 alkenyl, hydroxy, C 1 -C 6 alkoxy, amino, mercapto, oxo, and 3-6 membered heterocyclyl, wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; each of R L21 , R L22 , R L23 , and R L24 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C 2 -C 6 alkenyl, hydroxy, C 1 -C 6 alkoxy, amino, mercapto, and -(C 1 -C 6 alkylene)-N(C 1 -C 6 alkyl) 2 , wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; each of R b1 and R b3 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C 2 -C 6 alkenyl, hydroxy, C 1 -C 6 alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; W 1 is selected from N and CR 3 , wherein R 3 is selected from hydrogen, C 1 -C 6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, hydroxy, C 1 -C 6 alkoxy, amino, or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; and W 3 is selected from N and CR 4 , wherein each of R 4 is selected from hydrogen, C 1 -C 6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C 2 -C 6 alkenyl, hydroxy, C 1 -C 6 alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; and n is an integer between 2 to 7.
  9. The compound according to any one of claims 1 to 3, wherein the compound is a compound represented by Formula (Ic-3): (Ic-3) wherein: each of R a1 , R a2 , and R a3 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C 2 -C 6 alkenyl, hydroxy, C 1 -C 6 alkoxy, amino, mercapto, oxo, and 3-6 membered heterocyclyl, wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; each of R L21 , R L22 , R L23 , and R L24 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C 2 -C 6 alkenyl, hydroxy, C 1 -C 6 alkoxy, amino, mercapto, and -(C 1 -C 6 alkylene)-N(C 1 -C 6 alkyl) 2 , wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; each of R b1 and R b3 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C 2 -C 6 alkenyl, hydroxy, C 1 -C 6 alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; W 1 is selected from N and CR 3 , wherein R 3 is selected from hydrogen, C 1 -C 6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, hydroxy, C 1 -C 6 alkoxy, amino, or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; and W 3 is selected from N and CR 4 , wherein each of R 4 is selected from hydrogen, C 1 -C 6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C 2 -C 6 alkenyl, hydroxy, C 1 -C 6 alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; and n is an integer between 2 to 7.
  10. The compound according to any one of claims 1 to 3, wherein the compound is a compound represented by Formula (Ic-4): (Ic-4) wherein: wherein: each of R a1 , R a2 , R a3 , R a4 , and R a5 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C 2 -C 6 alkenyl, hydroxy, C 1 -C 6 alkoxy, amino, mercapto, oxo, and 3-6 membered heterocyclyl, wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; each of R L21 , R L22 , R L23 , and R L24 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C 2 -C 6 alkenyl, hydroxy, C 1 -C 6 alkoxy, amino, mercapto, and -(C 1 -C 6 alkylene)-N(C 1 -C 6 alkyl) 2 , wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; each of R b1 and R b3 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C 2 -C 6 alkenyl, hydroxy, C 1 -C 6 alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; W 1 is selected from N and CR 3 , wherein R 3 is selected from hydrogen, C 1 -C 6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, hydroxy, C 1 -C 6 alkoxy, amino, or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; and W 3 is selected from N and CR 4 , wherein each of R 4 is selected from hydrogen, C 1 -C 6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C 2 -C 6 alkenyl, hydroxy, C 1 -C 6 alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; and n is an integer between 2 to 7.
  11. The compound according to any one of claims 1 to 3, wherein the compound is a compound represented by Formula (Ic-5): (Ic-5) wherein: each of R a2 and R a3 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C 2 -C 6 alkenyl, hydroxy, C 1 -C 6 alkoxy, amino, mercapto, oxo, and 3-6 membered heterocyclyl, wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; each of R L11 , R L12 , and R L13 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C 2 -C 6 alkenyl, hydroxy, C 1 -C 6 alkoxy, amino, and mercapto; each of R b1 and R b3 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C 2 -C 6 alkenyl, hydroxy, C 1 -C 6 alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; W 1 is selected from N and CR 3 , wherein R 3 is selected from hydrogen, C 1 -C 6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, hydroxy, C 1 -C 6 alkoxy, amino, or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; W 3 is selected from N and CR 4 , wherein each of R 4 is selected from hydrogen, C 1 -C 6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C 2 -C 6 alkenyl, hydroxy, C 1 -C 6 alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; and n is an integer between 2 to 7.
  12. The compound according to any one of claims 1 to 3, wherein the compound is a compound represented by Formula (Ic-6): (Ic-6) wherein: each of R a1 , R a2 , and R a3 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C 2 -C 6 alkenyl, hydroxy, C 1 -C 6 alkoxy, amino, mercapto, oxo, and 3-6 membered heterocyclyl, wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; each of R b1 and R b3 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C 2 -C 6 alkenyl, hydroxy, C 1 -C 6 alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; W 1 is selected from N and CR 3 , wherein R 3 is selected from hydrogen, C 1 -C 6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, hydroxy, C 1 -C 6 alkoxy, amino, or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; W 3 is selected from N and CR 4 , wherein each of R 4 is selected from hydrogen, C 1 -C 6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C 2 -C 6 alkenyl, hydroxy, C 1 -C 6 alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; and n is an integer between 2 to 7.
  13. The compound according to any one of claims 1 to 3, wherein the compound is selected from the group consisting of:
  14. A pharmaceutical composition for preventing or treating diseases or disorders mediated by USP1, preferably cancer, more preferably lung cancer, non-small cell lung cancer (NSCLC), ovarian cancer, breast cancer, bladder cancer, CNS cancer, lymphoma, esophageal cancer, head and neck cancer, colorectal cancer, myeloma, sarcoma, gastric cancer, liver cancer, cervical cancer, brain cancer including glioma, glioblastoma, astrocytoma, medulloblastoma, and meningioma; skin cancer including melanoma, kidney cancer, colon cancer, osteosarcoma, pancreatic cancer, bone cancer, including chondrosarcoma; soft tissue cancer, including rhabdoid; or uterine cancer, comprising the compound according to any one of claims 1 to 13, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof; and a pharmaceutically acceptable carrier(s) or excipient(s).
  15. The pharmaceutical composition according to claim 14, wherein the composition is administered separately, sequentially or simultaneously with additional DNA damage response (DDR) targeting anti-cancer agent(s), preferably PARP inhibitors (e.g., niraparib, olaparib, rucaparib, talazoparib, veliparib, E7016), ATR inhibitors (e.g., VE-821, VE-822, VX-970 (also known as M6620 or berzosertib), AZD6738 (e.g., ceralasertib), BAY 1895344, M4344), ATM inhibitors (e.g., AZD0156, AZD0156, AZD1390, M3541), DNA-PK Inhibitors (e.g., CC-115, M3814 (nedisertib or peposertib), AZD7648), CHK1/2 Inhibitors (e.g., UCN-01, AZD7762, LY2603618, MK-8776, GDC-0575, LY2606368 (e.g., prexasertib)), WEE1 Inhibitors (e.g., Adavosertib (MK-1775, or AZD1775), PLK1 Inhibitors (e.g., Volasertib (BI 6727), Onvansertib (e.g., PCM-075, NMS-1286937), APE1 inhibitors (e.g., methoxyamine), or Topoisomerase inhibitors (e.g., belotecan, CRLX101, irinotecan, LMP 400, LMP 776, NKTR-102, doxorubicin, epirubicin, etoposide, idarubicin, mitoxantrone, teniposide).
  16. A compound according to any one of claims 1 to 13, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof for use in the prevention or treatment of diseases or disorders mediated by USP1, preferably cancer, more preferably lung cancer, non-small cell lung cancer (NSCLC), ovarian cancer, breast cancer, bladder cancer, CNS cancer, lymphoma, esophageal cancer, head and neck cancer, colorectal cancer, myeloma, sarcoma, gastric cancer, liver cancer, cervical cancer, brain cancer including glioma, glioblastoma, astrocytoma, medulloblastoma, and meningioma; skin cancer including melanoma, kidney cancer, colon cancer, osteosarcoma, pancreatic cancer, bone cancer, including chondrosarcoma; soft tissue cancer, including rhabdoid; or uterine cancer.
  17. The compound according to claim 16, wherein the compound is administered separately, sequentially or simultaneously with additional DNA damage response (DDR) targeting anti-cancer agent(s), preferably PARP inhibitors (e.g., niraparib, olaparib, rucaparib, talazoparib, veliparib, E7016), ATR inhibitors (e.g., VE-821, VE-822, VX-970 (also known as M6620 or berzosertib), AZD6738 (e.g., ceralasertib), BAY 1895344, M4344), ATM inhibitors (e.g., AZD0156, AZD0156, AZD1390, M3541), DNA-PK Inhibitors (e.g., CC-115, M3814 (nedisertib or peposertib), AZD7648), CHK1/2 Inhibitors (e.g., UCN-01, AZD7762, LY2603618, MK-8776, GDC-0575, LY2606368 (e.g., prexasertib)), WEE1 Inhibitors (e.g., Adavosertib (MK-1775, or AZD1775), PLK1 Inhibitors (e.g., Volasertib (BI 6727), Onvansertib (e.g., PCM-075, NMS-1286937), APE1 inhibitors (e.g., methoxyamine), or Topoisomerase inhibitors (e.g., belotecan, CRLX101, irinotecan, LMP 400, LMP 776, NKTR-102, doxorubicin, epirubicin, etoposide, idarubicin, mitoxantrone, teniposide).
  18. A method of treating or preventing diseases or disorders mediated by USP1 in a subject, comprising administering to the subject at least one compound according to any one of claims 1 to 13, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof.
  19. The method of claim 18, wherein the diseases or disorders mediated by USP1 are cancer, preferably lung cancer, non-small cell lung cancer (NSCLC), ovarian cancer, breast cancer, bladder cancer, CNS cancer, lymphoma, esophageal cancer, head and neck cancer, colorectal cancer, myeloma, sarcoma, gastric cancer, liver cancer, cervical cancer, brain cancer including glioma, glioblastoma, astrocytoma, medulloblastoma, and meningioma; skin cancer including melanoma, kidney cancer, colon cancer, osteosarcoma, pancreatic cancer, bone cancer, including chondrosarcoma; soft tissue cancer, including rhabdoid; or uterine cancer.
  20. The method of any one of claims 18 to 19, further comprising administering to the subject additional DDR targeting anti-cancer agent(s), preferably PARP inhibitors (e.g., niraparib, olaparib, rucaparib, talazoparib, veliparib, E7016), ATR inhibitors (e.g., VE-821, VE-822, VX-970 (also known as M6620 or berzosertib), AZD6738 (e.g., ceralasertib), BAY 1895344, M4344), ATM inhibitors (e.g., AZD0156, AZD0156, AZD1390, M3541), DNA-PK Inhibitors (e.g., CC-115, M3814 (nedisertib or peposertib), AZD7648), CHK1/2 Inhibitors (e.g., UCN-01, AZD7762, LY2603618, MK-8776, GDC-0575, LY2606368 (e.g., prexasertib)), WEE1 Inhibitors (e.g., Adavosertib (MK-1775, or AZD1775), PLK1 Inhibitors (e.g., Volasertib (BI 6727), Onvansertib (e.g., PCM-075, NMS-1286937), APE1 inhibitors (e.g., methoxyamine), or Topoisomerase inhibitors (e.g., belotecan, CRLX101, irinotecan, LMP 400, LMP 776, NKTR-102, doxorubicin, epirubicin, etoposide, idarubicin, mitoxantrone, teniposide).

Description

SUBSTITUTED SPIRO COMPOUND DERIVATIVES AND THEIR PHARMACEUTICAL USE The present disclosure belongs to a technical field of medicine, and particularly relates to spiro compound derivates with inhibitory effect on USP1, pharmaceutical compositions containing the same, and preparation methods and uses thereof. Ubiquitin is a highly conserved polypeptide composed of 76 amino acids residues. It is conjugated to a substrate protein as part of a post-translational modification, which is known as a ubiquitination process. During the ubiquitination process, ubiquitin is attached to lysine residues on the substrate protein or itself, leading to monoubiqutination or polyubiquitination. Ubiquitination plays a critical role in the regulation of protein stability, function, and localization, and thus, it is involved in various cellular processes, including immune response, cell proliferation, DNA repair, etc. Ubiquitination is a reversible process due to the presence of deubiquitination enzymes (DUBs), which can remove ubiquitin from the substrate protein. USP1 (Ubiquitin specific protease 1) is one of deubiquitination enzymes, and is known to play an important role in the regulation of DNA repair processes. In order to gain deubiquitanase activity, USP1 is associated with UAF1 (USP1-associated factor 1) to form a heterodimeric USP1/UAF1 complex. The USP1/UAF1 complex regulates the following two cellular pathways: Faconi anemia (FA) pathway and translesion synthesis (TLS) pathway. In the FA pathway, the USP1/UAF1 complex deubiquitinates monoubiqutinated FANCD2 (Fanconi anemia group complentation group D2) and FANC1 (Fanconi anemia complementation group 1) proteins. In the TLS pathway, the USP1/UAF1 complex deubiquitinates monoubiqutinated PCNA (proliferating cell nuclear antigen). The above-mentioned two pathways are known to participate in repairing DNA damage caused by DNA interstand crosslink (ICL). Inhibition of USP1 can impair DNA damage response, mainly in the FA and TLS pathways. Based on the above-described mechanism, USP1 has been identified as a promising therapeutic target for various cancers. For example, it has been shown that USP1 inhibitors reverse cisplatin resistance in non-small cell lung cancer (NSCLC) (Chen, J., et al, 2011, Chemistry & biology, 1390-1400). It has also been shown that USP1 inhibition inhibits tumor growth in osteosarcoma cells (Williams, Samuel A., et al., 2011, Cell, 146(6), 918-930; and Lim, K. H & Baek, K. H., 2013, Current pharmaceutical design, 19(22), 4039-4052), and leukemic cells (Mistry, Helena, et al., 2013, Molecular cancer therapeutics 12.12 (2013): 2651-2662). Therefore, inhibiting USP1 has potential as a treatment for various cancers, and there is a need to develop novel small molecule compounds that have an inhibitory activity for USP1. Compounds According to an aspect of the present disclosure, provided is a compound of Formula (I), (including subsets of each formula), or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof. As used herein, "compound of the present disclosure" refers to the following compound of Formula (I) (including subsets of each formula), or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof. In one embodiment, the present disclosure relates to a compound of Formula (I): (I) wherein: A is 5-12 membered heteroaryl or 5-12 membered heterocyclyl, wherein each of said heteroaryl and heterocyclyl is independently optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, amino, mercapto, oxo, 3-6 membered heterocyclyl, and RL1, wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; L is selected from the group consisting of -(C2-C6 alkynylene)-, -(6-14 membered arylene)-, -(7-11 membered polycyclic cycloalkylene)-, -(C2-C6 alkynylene)-NH-, -(6-14 membered arylene)-NH-, and -(7-11 membered polycyclic cycloalkylene)-NH-, wherein said arylene is optionally substituted with one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, amino, mercapto, -(C1-C6 alkylene)-N(C1-C6 alkyl)2, and RL2, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; RL1 and RL2, taken together with the atoms to which each RL1 and RL2 is attached, form a saturated or unsaturated 5-10 membered carbocyclic or heterocyclic group, wherein said carbocyclic or heterocyclic group is optionally substituted with one o