Compound having novel structure as ubiquitin-specific protease 1 (USP1) inhibitor and pharmaceutical composition comprising same

Abstract

The present invention relates to a compound having a novel structure and ubiquitin-specific protease 1 (USP1) inhibitory activity, a stereoisomer thereof, or pharmaceutically acceptable salts thereof, use thereof for preparing a therapeutic drug, a pharmaceutical composition containing same, a therapeutic use and method using the composition, and a method for preparing same. The compound having a novel structure and USP1 inhibitory activity is represented by Formula Ia, Ib, or Ic.

Claims

【Scope of Claim】

1. A compound represented by any one of the following formulas la to Ic, a stereoisomorph thereof, or a pharmaceutically acceptable salt thereof: [Formula la] In any one of the above chemical formulas la, lb, and Ic, Z1 to Z6 are each independently N or CQ, where Q is X, H, 2 H, R, —OR, NH2, -NHR, -N(R)2, -C(=O), — C(=0)— R, -COOR, -C(=O)-NH2, -C(=O)-NHR or - C(=o)- N(R)2, and ® is a pentagonal or hexaagonal heteroaryl containing 1 to 4 heteroatoms independently selected from the group consisting of C6-C12 aryls or N, O, and S within the ring, and Ri are independently X, H, 2 H, R, -OR, -NH2, -NHR, — N(R)2, — C(=0)— R, - COOR, -C(=O)-NH2, -C(=O)-NHR or - C(=0)- N(R)2, where , one or more of R are X or 2 It is substituted or unsubstituted with H, and R2 and R3 are each independently X, H, 2 H, R, -OR, -NH2, -NHR or -N(R)2 is, and CD is a pentagonal or hexavalent heterocycloalkyl containing 1 to 4 heteroatoms independently selected from the group consisting of N, O, and S in the ring, a C6-Ci2 aryl, or a pentagonal or hexavalent heteroaryl containing 1 to 4 heteroatoms independently selected from the group consisting of N, O, and S, and one or more members of the C6-C12 aryl of the AO or the pentagonal or hexavalent heteroaryl containing 1 to 4 heteroatoms independently selected from the group consisting of N, O, and are each independently substituted or unsubstituted with X or Ci-C6 alkyl, and R4 each independently X, H, 2 H, R, -OR, -NH2, -NHR, -N(R)2 or -C(=O)R, where one or more of R are X or 2 It is substituted or unsubstituted with H, R5 is independently selected from the group consisting of C6-C12 aryls or N, O, and It is a quinaryl or six-membered heteroaryl containing 1 to 4 heteroatoms in the ring, wherein one or more H of R5 are each independently substituted or unsubstituted with a quinaryl to seven-membered heterocycloalkyl containing 1 to 4 heteroatoms in the ring, independently selected from the group consisting of X, Cl-C6alkyl, C3-C7cycloalkyl, N, O, and S; -(Ci-C5alkylene)-(quinaryl to seven-membered heterocycloalkyl containing 1 to 4 heteroatoms in the ring, independently selected from the group consisting of N, O, and), -0(Ci-C6alkyl), or -0(quinaryl to seven-membered heterocycloalkyl containing 1 to 4 heteroatoms in the ring, independently selected from the group consisting of N, O, and), wherein Ci-C6alkyl, N, O, and One or more Hs of a 5- to 7-membered heterocycloalkyl containing 1 to 4 heteroatoms independently selected from the group consisting of S within the ring are each independently X, 2 H, -OH or Ci- C6 alkyl substitution or non-substitution, D is - N=S(=0)R6R7 and, R6 and R7 each independently X, H, 2 H, R, -OR, -SR, -NH2, -NHR, -N(R)2, -CN, or -C(=O)R, wherein R6 and R7 are optionally connected to each other to form a quaternary to 12-membered heterocycloalkyl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S within the ring, or a quaternary to 12-membered heterocycloalkenyl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S within the ring. R comprises 1 to 4 heteroatoms within the ring, each independently selected from the group consisting of Ci-C6 alkyl, C3-C7 cycloalkyl, N, O, and S. It is a 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of 5- to 7-membered heterocycloalkyls, C6-C12-aryls, or N, O, and S within the ring, wherein m and n are each independently 0, 1, 2, or 3, and X is F, Cl, Br, or I.

1. A compound represented by any one of the formulas la to Ic, wherein in any one of the formulas la, lb, and Ic, Zi to Z6 are each independently N or CQ, where Q is X, H, or an arc; a stereoisomer thereof; or a pharmaceutically acceptable salt thereof. 【claim [Clause 3] In claim 1, in any one of the formulas la, lb, and Ic, the AO is a pentagonal or hexaryl containing 1 to 4 Ns within the ring, and A compound represented by any one of the formulas la to Ic, wherein Ri is independently Ci-C6 alkyl, C3-C7 cycloalkyl, -0 (Ci-C6 alkyl), or -0 (C3-C7 cycloalkyl), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. 【In Claim 1, in any one of the above chemical formulas la, lb, and Ic, R2 and R3 are each independently X, H, or C1-C6 alkyl, and G) is a C6-C12 aryl or a pentatonic group containing 1 to 4 Ns in the ring. 288 or is a 6-membered heteroaryl, wherein one or more H of the C6-C12 aryl of the above AO are each independently substituted or unsubstituted with X or a C1-C6 alkyl, and R4 is independently X, H, or C1-C6 alkyl, and A compound represented by any one of the formulas la to Ic, stereoisomers thereof, or pharmaceutically acceptable salts thereof, wherein R5 is a pentagonal or six-membered heteroaryl containing 1 to 4 ni-rings, and one or more of the R5 members are each independently substituted or unsubstituted with X, -CX3, -CX2H, Cl-C6alkyl, c'c7cycloalkyl, or -O(C1-C6alkyl). 【claim [Clause 5] In Clause 1, in any one of the above chemical formulas la, lb, and Ic, R6 and R7 are independently H, X, R, -OR, -SR, NH2, -NHR, -N(R)2, -CN, or -C(=O)R, and Z7 is a single bond (a bond), O, CH, NH, O or , and One or more of Z7's beams are each independently X, R, -OR, NH2, -NHR, -N(R)2, - Substitute with C(=O)R, - S(=0)2R, - C(=O)OR, -C(=O)-NH2, -C(=O)-NHR, or - C(=0)N(R)2. A compound represented by any one of the formulas la to Ic, which is or is not substituted, and where a, b, c and ger are each independently 1, 2, or 3; a stereoisomer thereof; or a pharmaceutically acceptable salt thereof. [In Claim Paragraph 5, R6 and R7 are each independently H, X, Ci-C6alkyl, C3-C7cycloalkyl, C6-C12aryl, -NH2, -NH(Ci-C6alkyl) or -N(Ci-C6alkyl) 2, and Z7 is a single bond (a bond), CH2, CH, NH, or 0, and A compound represented by any one of the formulas la to Ic, stereoisomers thereof, or pharmaceutically acceptable salts thereof, wherein one or more H of Z7 are each independently substituted or unsubstituted with X, Ci-C6alkyl, -C(=O)(Ci-C6alkyl), or -S(=O)2(C1-C6alkyl).

7. The compound represented by any one of the formulas la to Ic, stereoisomers thereof, or pharmaceutically acceptable salts thereof, wherein Zi to Z6 are each independently N or eu, and Q is X, H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, or cyclobutyl. 【claim [Clause 8] In Paragraph 1, 290 A compound represented by any one of the formulas la to Ic, stereoisomers thereof, or pharmaceutically acceptable salts thereof, wherein Z1 and Z3 are each independently N or CQ, where Q is X, H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, or cyclobutyl. [In Claim Paragraph 3, It is a pyrimidine matter, A compound represented by any one of the formulas la to Ic, wherein R1 is independently methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, -0(methyl), -0(ethyl), -o(n-propyl), -0(isopropyl), -0(cyclopropyl), or -0(cyclobutyl), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

10. [I] In Article 4, R2 and R3 are each independently X or O, the above © is phenyl or pyridinyl, and one or more H of the phenyl group of the above CD are each independently substituted with X or unsubstituted, and R4 is visible, A compound represented by any one of the formulas la to Ic, stereoisomers thereof, or pharmaceutically acceptable salts thereof, wherein R5 is an imidazole, a pyrazole, or a pyridine, and one or more of the R5 are each independently substituted or unsubstituted with methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, -0(methyl), or -CF3.

11. In Claim 6, R6 and R7 are each independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, phenyl, or -N(CH3)2, and Z7 is a single bond (a bond), CH2, CH, NH, or 0, and A compound represented by any one of the formulas la to Ic, wherein one or more of Z7 are each independently substituted or unsubstituted with X, methyl, ethyl, n-propyl, isopropyl, -C(=O)(CH3) or -S(=O)2(CH3), and a, b, c and ger are each independently 1 or 2, and stereoisomers thereof. 292 Or their pharmaceutically acceptable salts.

12. A compound represented by any one of the following formulas Ha to He, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [Chemical Formula Ila] In any one of the above chemical formulas Ila, Hb, and He, Zi and Z3 are each independently N or CQ, where this means X, H, or R as, CD is a pentagonal or hexaryl containing 1 to 4 sieves within a ring, and Ri are each independently Ci-C6alkyl, C3-C7cycloalkyl, -O(Ci-C6alkyl), or - 0 (C3-C7 cycloalkyl), and R2 and R3 are each independently X, H, or C1-C6 alkyl, and It is a pentagonal or hexaagonal heteroaryl contained within, wherein one or more H of the C—ryl of the above © are each independently substituted or unsubstituted with X or alkyl, and R4 is independently X, H, or C1-C6 alkyl, and R5 is a pentagonal or hexagonal heteroaryl contained within 1 to 4 niole rings, and one or more of the R5 members are each independently X, -CX3, -CX2H, CI-C6alkyl, It is substituted or unsubstituted with C3-C7 cycloalkyl or -0 (Ci-C6 alkyl), and R6 and R7 are each independently H, X, Cl- C6 alkyl, C3-C7 cycloalkyl, C6-C12 a ril - NH2, -NH(C1-C6 alkyl) or - N(C1-C6 alkyl) 2, and Z7 is a single bond (a bond), CH2, CH, NH, or 0, and One or more H of Z7 are each independently substituted or unsubstituted with X, Ci-C6alkyl, -C(=O)(Ci-C6alkyl) or -S(=O)2(C1-C6alkyl), and R is a 5- to 7-membered heterocycloalkyl containing 1 to 4 heteroatoms in the ring independently selected from the group consisting of Ci-C6alkyl, C3-C7cycloalkyl, N, O, and S, a C6-C12-aryl, or a 5-membered or 6-membered heteroaryl containing 1 to 4 heteroatoms in the ring selected from the group consisting of N, O, and S, m and n are each independently 0, 1, or 2, and a, b, c, and ger are each independently 1 or 2, and X is F, Cl, Br, or I.

13. In Claim 12, in any one of the formulas Ila, lib, and He, Zi and Z3 are each independently N or CQ, where Q is X, H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, or cyclobutyl, and A is a pyrimidine, and Ri is independently methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, -0(methyl), -0(ethyl), -0(n-propyl), -0(isopropyl), -0(cyclopropyl), or -0(cyclobutyl), and R2 and R3 are each independently X or O, and 295 Dinyl is present, and one or more H of the phenyl group of <2> are each independently substituted with or unsubstituted with X, and R4 is visible, and R5 is an imidazole yl, a pyrazole yl, or a pyridine yl, and one or more of the visible of R5 are each independently substituted or unsubstituted with methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, -0(methyl), or -CF3, and R6 and R7 are each independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, phenyl, or -N(CH3)2, and Z7 is a single bond (a bond), CH2, CH, NH, or 0, and A compound represented by any one of the formulas Ila to He, wherein one or more of Z7 are each independently substituted or unsubstituted with X, methyl, ethyl, n-propyl, isopropyl, -C(=0)(CH3) or -S(=0)2(CH3), and a, b, c and ger are each independently 1 or 2, stereoisomers thereof, or pharmaceutically acceptable salts thereof.

14. In Claim 13, the above-mentioned days are each independently A compound represented by any one of the chemical formulas Ila to He, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

15. The following compounds 1 to 112, stereoisomers thereof, or pharmaceutically acceptable salts thereof:

16. A pharmaceutical composition for the prevention or treatment of diseases related to ubiquitin-specific protease 1 (Ubiquitin-specific Protease 1 Inhibitor, USP1) activity, comprising as an active ingredient a compound represented by any one of the formulas la to Ic and Ila to He according to any one of claims 1 to 15, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

17. The pharmaceutical composition of Claim 16, wherein the pharmaceutical composition exhibits ubiquitin-specific protease 1 (Ubiquitin-specific Protease 1 Inhibitor, USP1) inhibitory activity.

18. The pharmaceutical composition of Claim 16, wherein the ubiquitin-specific protease 1 (USP1) activity-related diseases include cancer, benign neoplasms, angiogenesis, inflammatory diseases, and autoimmune diseases. 307 water

19. The invention of Claim 18, wherein the cancer is hematological cancer, lymphoma, myeloma, leukemia, neurological cancer, skin cancer, breast cancer, prostate cancer, colorectal cancer, lung cancer, head and neck cancer, gastrointestinal cancer, liver cancer, pancreatic cancer, genitourinary cancer, bone cancer, renal cancer, vascular cancer, human immunodeficiency virus (HIV) associated solid tumors, human papillomavirus-positive intractable A pharmaceutical composition comprising solid tumors (human papillomavirus (HPV)-16 positive incurable solid tumors), adult T-cell leukemia, gastric cancer, nasopharyngeal carcinoma, cervical cancer, vaginal cancer, vulvar cancer, squamous cell carcinoma of the head and neck, and Merkel cell carcinoma.

20. A method for treating a disease associated with ubiquitin-specific protease 1 (USP1) activity comprising administering a therapeutically effective amount of a compound represented by any one of the formulas la to Ic and Ila to He according to any one of claims 1 to 15, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. 308

21. Use for the prevention or treatment of diseases associated with ubiquitin-specific protease 1 (USP1) activity of a compound represented by any one of formulas la to Ic and formulas I la to He according to any one of claims 1 to 15, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

22. Formulas la to Ic and formulas according to any one of Claims 1 to 15 Use for the preparation of a drug for the prevention or treatment of a disease associated with ubiquitin-specific protease 1 (USP1) activity of a compound represented by any one of I to He, stereoisomers thereof, or pharmaceutically acceptable salts thereof.

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