WO2025129135A2 - Compositions comprenant des inhibiteurs d'usp1 et leurs méthodes d'utilisation - Google Patents

Compositions comprenant des inhibiteurs d'usp1 et leurs méthodes d'utilisation Download PDF

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WO2025129135A2
WO2025129135A2 PCT/US2024/060229 US2024060229W WO2025129135A2 WO 2025129135 A2 WO2025129135 A2 WO 2025129135A2 US 2024060229 W US2024060229 W US 2024060229W WO 2025129135 A2 WO2025129135 A2 WO 2025129135A2
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ring
alkyl
haloalkyl
alkynyl
haloalkoxy
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WO2025129135A3 (fr
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Paul Andrew ALLEGRETTI
Hilary Plake BECK
Tom Tuan LUONG
Adon Calvin KWONG
Joseph S. CAPANI, Jr.
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Eikon Therapeutics Inc
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Eikon Therapeutics Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • compositions and methods described herein relate to compositions comprising USP1 inhibitors and methods of their use in treating disease, e.g., cancer.
  • compositions and methods described herein relate to a compound of formula (I) or a pharmaceutically acceptable salt thereof: wherein: R 1 is selected from C3-C8 cycloalkyl ring, C 6 -C 10 aryl, or 4-, 5-, 6-, or 7- membered heterocyclyl ring, and C 6 -C 10 aryl fused with 3-8 membered heterocyclic group; wherein R 1 is optionally substituted with one or more groups selected from - OH, -COOH, -NH 2 , -CN, halogen, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, -OCD3, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 6-10 aryl, 5-8 membered heteroaryl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, -O-C 1-6 alkyl, -O-
  • ring A when ring A is a 5-membered heteroc cl l rin and at least one heteroatom is S, ring A is selected from , , or , where Z is N; wherein when ring A is selected from or , Z is N, and R 2 is where S and P are N, wherein: (i) when S or P are substituted with C1 alkyl then R 1 is C 6 -C 10 aryl; (ii) S or P are substituted with one or more groups selected from -OH, -COOH, - NH2, -CN, -CD(CD3)2, halogen, C 2-6 alkyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, and C3-C8 cycloalkyl; or (iii) V or W are substituted with one or more groups selected from -OH, -COOH, -NH2,
  • the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein R 1 is selected from C 3 -C 8 cycloalkyl ring, C 6 -C 10 aryl, or 4-, 5-, 6-, or 7- membered heterocyclyl ring, and C 6 -C 10 aryl fused with 3-8 membered heterocyclic group; and wherein R 1 is optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, halogen, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, -OCD3, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 6-10 aryl, 5-8 membered heteroaryl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, -O-C 1-6 alkyl, -O- C 1-6 alkylene
  • the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein R 1 is selected from C 6 aryl, 5- or 6-memered heterocyclic ring and C 6 aryl fused with 5-membered heterocyclic group; and wherein R 1 is optionally substituted with one or more groups selected from -OH, -COOH, - NH2, -CN, halogen, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, -OCD3, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 6-10 aryl, 5-8 membered heteroaryl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, -O-C 1-6 alkyl, -O-C 1-6 alkylene, -O-C 1-6 haloalkyl, -NH-C 1-6 alkyl, and -NH-C
  • the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein R 1 is selected from: In certain embodiments, the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein when R 2 is , , , and ; and R 3 is selected from H, D, -OH, -COOH, -NH2, -CN, halogen, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and C 1-6 hydroxyalkyl; Z, U, V, W, P, Q, S, and T are independently selected from C, O, N, and S, wherein Z, U, V, W, P, Q, S, and T are optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, -CD(CD3)2, halogen, C1- 6 al
  • the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof:wherein R 2 is , Z is selected from C, O, N, and S; and R 3 is selected from H, D, -OH, -COOH, -NH 2 , -CN, halogen, C 1- 6 alkyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and C 1-6 hydroxyalkyl; wherein the phenyl ring is optionally substituted with one or more groups selected from - OH, -COOH, -NH2, -CN, halogen, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, and C 3 -C 8 cycloalkyl ring.
  • the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein R 2 is selected from: , , and .
  • the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein R 2 is and the 5 or 6 membered ring is saturated or unsaturated;
  • R3 is selected from H, D, -OH, -COOH, - NH2, -CN, halogen, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and C 1-6 hydroxyalkyl;
  • Z, U, V, W, P, Q, S, and T are independently selected from C, O, N, and S; wherein Z, U, V, W, P, Q, S and T are optionally substituted with one or more groups selected from -OH, -COOH, -NH 2 , -CN,
  • the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein R 2 is , and the 5-membered ring is saturated or unsaturated; R3 is selected from H, D, -OH, -COOH, -NH2, -CN, halogen, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and C 1-6 hydroxyalkyl; and Z, P, Q, and S are independently selected from C, O, N, and S; wherein Z, P, Q, and S are optionally substituted with one or more groups selected from -OH, - COOH, -NH2, -CN, halogen, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, and C 3 -
  • the present disclosure is directed to a compound of formula (I) or a pharmaceutically acceptable salt thereof: wherein R 2 is selected from: , , , and .
  • the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein R 2 is , and is saturated or unsaturated; Z, P, Q, and S are independently selected from C, O, N, and S, wherein Z, P, Q, and S are optionally substituted with one or more groups selected from - OH, -COOH, -NH2, -CN, halogen, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, and C 3 -C 8 cycloalkyl ring.
  • the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein R 2 is selected from: , , and . In certain embodiments, the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein X 1 is selected from C and N.
  • the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein X 2 is selected from C and N; wherein when X 2 is C, the said C is optionally substituted with hydrogen, halogen, -CN, - OR 4 , -SR 4 , -N(R5)2, C 1-6 alkyl, C 1-6 haloalkyl, wherein R 4 and R5 are independently selected from C 1 -C 6 alkyl.
  • the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein when ring A contains ring carbon atoms and one or more heteroatoms, the heteroatoms are selected from N and S wherein when ring A is a 5-membered heterocyclyl ring and contains one heteroatom selected from N, ring A is selected from , , and ; wherein when ring A is and R 2 is , V and W are optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, -CD(CD3)2, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, and C 3 -C 8 cycloalkyl ring; wherein when ring A is and Z is O, ring A is optionally substituted with one or more groups selected from -OH, -COOH
  • the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein when ring A is a 5-membered heterocyclyl ring and at least one heteroatom is S, ring A is selected from , , or , where Z is N; wherein when ring A is selected from or , Z is N, and R 2 is where S and P are N, wherein: (i) when S or P are substituted with C1 alkyl then R 1 is C 6 -C 10 aryl; (ii) S or P are substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, -CD(CD3)2, halogen, C 2-6 alkyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, and C3-C8 cycloalkyl; or (iii) V or W are substitute
  • the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein when ring A contains ring carbon atoms and one or more heteroatoms, the heteroatoms are selected from N and S; wherein when ring A is a 5-membered heterocyclyl ring and contains one heteroatom selected from N, ring A is selected from , , and ; wherein when ring A is and R 2 is , V and W are optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, -CD(CD3)2, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, and C3-C8 cycloalkyl ring; wherein when ring A is and Z is O, ring A is optionally substituted with one or more groups selected from -OH, -COOH
  • the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein when ring A is a 5-membered heterocyclyl ring and at least one heteroatom is S, ring A is selected from , , or , where Z is N; wherein when ring A is selected from or , Z is N, and R 2 is where S and P are N, wherein: (i) when S or P are substituted with C1 alkyl then R 1 is C 6 -C 10 aryl; (ii) S or P are substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, -CD(CD3)2, halogen, C 2-6 alkyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, and C3-C8 cycloalkyl; or (iii) V or W are substitute
  • the present disclosure is directed to a compound of formula (I) or a pharmaceutically acceptable salt thereof: wherein ring A is selected from:
  • the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein ring A is . In certain embodiments, the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein the compound is selected from:
  • compositions and methods described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein: X’ and X” are independently selected from N or C; R 1 is wherein Z is selected from O or N optionally substituted with R 1 a or -CH2R 1 a, wherein R 1 a is C3-C 6 cycloalkyl or 4-, 5-, or 6- membered heterocyclyl; wherein R 2 is selected from H or d euterium; R3 is selected from , , and , wherein W is selected from C or N, and wherein R3a, R3b, and R3c are independently selected from - H or halogen, R 3a and R 2 optionally form a bond to form a 5- or 6-membered heterocyclyl, or R 3 and R 3b optionally combine to form a bridge; R 4 is selected from , , , , , , and , wherein U and Y are independently selected from C or
  • compositions and methods described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein R 1 is wherein Z is selected from O or N optionally substituted with R 1 a or -CH2R 1 a, wherein R 1a is C 3 -C 6 cycloalkyl or 4-, 5-, or 6- membered heterocyclyl; wherein R 2 is selected from H or deuterium; R3 is selected from , and , wherein W is selected from C or N, and wherein R3a, R3b, and R3c are independently selected from -H or halogen, R 3a and R 2 optionally form a bond to form a 5- or 6-membered heterocyclyl, or R3a and R3b optionally combine to form a bridge; R 4 is selected from , , , , , , , and , wherein U and Y are independently selected from C or N, and wherein when U is N, Y is C, and when U
  • compositions and methods described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein R3 is s elected from , , and , wherein W is selected from N or C.
  • the compositions and methods described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein R3 is selected from , , , , and .
  • the compositions and methods described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein when R3a and R 2 form a bond to form a 5- or 6-membered heterocyclyl, R 3 is .
  • compositions and methods described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein when R 3a and R3b combine to form a bridge, R3 is .
  • compositions and methods described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein R 4 is selected from , , , , , , , and , wherein U and Y are independently selected from C or N, and wherein when U is N, Y is C, and when U is C, Y is N or C; wherein R5, R6, and R7 are independently selected from -H, -OH, -COOH, -NH 2 , -CN, halogen, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C3-C8 cycloalkyl
  • compositions and methods described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein R 4 is , , , , and .
  • compositions and methods described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein when R3 is , R 1 is selected from:
  • compositions and methods described herein relate to a compound of formula (II) or a pharmaceutically acceptable salt thereof: wherein when R 3 is , R 1 is .
  • compositions and methods described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein when R 3 is , R 1 is .
  • compositions and methods described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein when R3 is , R 1 is .
  • the compositions and methods described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein when R 3 is , R 1 is selected from and .
  • compositions and methods described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein when R3a and R 2 form a bond to form a 5- or 6-membered heterocyclyl, R 1 is .
  • compositions and methods described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein when R3a and R 3b combine to form a bridge, R 1 is .
  • compositions and methods described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein ring A is a 5- or 6- membered heterocyclyl ring comprising one to three heteroatoms selected from N, O, or S; wherein when ring A is a 5-membered heterocyclyl ring and contains one heteroatom, ring A is selected from where X’ and X” are C and where X’ and X” are C; wherein when ring A is where X’ and X” are C, R 4 is , and Z is O, R 7 is selected from -H, -OH, -COOH, -NH 2 , -CN, halogen, C 3-6 alkyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 4 -C 8 cycloalkyl ring,
  • compositions and methods described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein Ring A is a 5- membered heterocyclyl ring comprising one to three heteroatoms selected from N, O, or S; wherein when ring A is a 5-membered heterocyclyl ring and contains one heteroatom, ring A is selected from where X’ and X” are C and where X’ and X” are C; wherein when ring A is where X’ and X” are C, R 4 is , and Z is O, R 7 is selected from -H, -OH, -COOH, -NH 2 , -CN, halogen, C 3-6 alkyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C4-C8 cycloalkyl ring, and 4-, 5- , or 6- member
  • compositions and methods described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein ring A is selected from: and .
  • compositions and methods described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein Ring A is a 6- membered heterocyclyl ring comprising one to three heteroatoms selected from N, O, or S; wherein when R ring A is 6-membered heterocyclyl ring, ring A is where X’ and X” are C and Z is N; wherein when ring A is where X’ and X” are C and R 4 is , R7 is selected from -H, -OH, -COOH, -NH2, -CN, halogen, C 2-6 alkyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl,
  • compositions and methods described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein ring A is .
  • compositions and methods described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein the compound is selected from:
  • present disclosure is directed to a method of modulating USP1 activity in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • the present disclosure is directed to a method of inhibiting USP1 activity in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • the present disclosure is directed to a method of treating a disorder or disease with a USP1 inhibitor in a subject, comprising administering to the subject a therapeutically effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • the present disclosure is directed to a method of treating cancer with a USP1 inhibitor in a subject, comprising administering to the subject a therapeutically effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • the present disclosure is directed to a method of treating cancer with a USP1 inhibitor in a subject, comprising administering a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the cancer is characterized by over expression of USP1.
  • the present disclosure is directed to a method treating cancer with a USP1 inhibitor in a subject, comprising administering a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the cancer characterized by overexpression of USP1 is selected from prostate, breast, ovarian, non-small cell lung cancer, mesothelioma, Merkel cell carcinoma, synovial sarcoma, renal cell carcinoma, and osteosarcoma.
  • the present disclosure is directed to a use of a compound of formula (I), or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer.
  • the present disclosure is directed to a use of a compound of formula (I), or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer, wherein the cancer is characterized by overexpression of USP1.
  • the present disclosure is directed to a process to manufacture a compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • FIG.1 shows the mean tumor volume over a period of time in mice treated with 30 mg/kg and 100 mg/kg of Compound 12.
  • FIG.2 shows the mean tumor volume over a period of time in mice treated with 30 mg/kg and 100 mg/kg of Compound 21.
  • FIG.3 shows the mean tumor volume over a period of time in mice treated with 30 mg/kg and 100 mg/kg of Compound 129.
  • FIG.4 shows the mean tumor volume over a period of time in mice treated with 30 mg/kg and 100 mg/kg of Compound 133.
  • DETAILED DESCRIPTION The presently disclosed subject matter relates to compositions comprising USP1 inhibitors and methods of their use in treating cancer. For purposes of clarity of disclosure and not by way of limitation, the detailed description is divided into the following subsections: 1. Definitions 2.
  • compositions of Matter 3. Methods of Use 4. Examples 1.
  • the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0-7.0, the number 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly contemplated.
  • the term “about” or “approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean within 3 or more than 3 standard deviations, per the practice in the art.
  • “about” can mean a range of up to 20%, preferably up to 10%, more preferably up to 5%, and more preferably still up to 1% of a given value.
  • the term can mean within an order of magnitude, preferably within 5-fold, and more preferably within 2-fold, of a value.
  • modulate or “modulating” refers to increasing or decreasing, e.g., modulation of the activity of an enzyme includes increasing the activity of the enzyme as well as decreasing the activity of the enzyme.
  • alkyl includes both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms and may be unsubstituted or substituted.
  • C 1 -C n as in “C 1 -C n alkyl” is defined to include groups having 1, 2, ...., n-1 or n carbons in a linear or branched arrangement.
  • C 1 -C 6 is defined to include groups having 1, 2, 3, 4, 5, or 6 carbons in a linear or branched arrangement, and specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, pentyl, hexyl, and octyl.
  • alkenyl refers to a non-aromatic hydrocarbon radical, straight or branched, containing at least 1 carbon to carbon double bond, and up to the maximum possible number of non-aromatic carbon-carbon double bonds may be present, and may be unsubstituted or substituted.
  • C 2 -C 6 alkenyl means an alkenyl radical having 2, 3, 4, 5, or 6 carbon atoms, and up to 1, 2, 3, 4, or 5 carbon-carbon double bonds respectively.
  • Alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl.
  • alkynyl refers to a hydrocarbon radical straight or branched, containing at least 1 carbon to carbon triple bond, and up to the maximum possible number of non- aromatic carbon-carbon triple bonds may be present, and may be unsubstituted or substituted.
  • C 2 -C 6 alkynyl means an alkynyl radical having 2 or 3 carbon atoms and 1 carbon-carbon triple bond, or having 4 or 5 carbon atoms and up to 2 carbon-carbon triple bonds, or having 6 carbon atoms and up to 3 carbon-carbon triple bonds.
  • Alkynyl groups include ethynyl, propynyl and butynyl.
  • heteroalkyl includes both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms and at least 1 heteroatom within the chain or branch.
  • cycloalkyl shall mean cyclic rings of alkanes of three to eight total carbon atoms, or any number within this range (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl).
  • heterocyclyl or “heterocyclic” refers to a mono- or poly- cyclic ring system which can be saturated or contains one or more degrees of unsaturation and contains one or more heteroatoms.
  • Preferred heteroatoms include N, O, and/or S, including N-oxides, sulfur oxides, and dioxides.
  • the ring is three to ten- membered and is either saturated or has one or more degrees of unsaturation.
  • the heterocycle may be unsubstituted or substituted, with multiple degrees of substitution being allowed.
  • Such rings may be optionally fused to one or more of another “heterocyclic” ring(s), heteroaryl ring(s), aryl ring(s), or cycloalkyl ring(s).
  • heterocycles include, but are not limited to, tetrahydrofuran, pyran, 1,4-dioxane, 1,3-dioxane, piperidine, piperazine, pyrrolidine, morpholine, thiomorpholine, tetrahydrothiopyran, tetrahydrothiophene, 1,3- oxathiolane, and the like.
  • the alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl substituents may be substituted or unsubstituted, unless specifically defined otherwise.
  • aryl is intended to mean any stable monocyclic, bicyclic or polycyclic carbon ring of up to 10 atoms in each ring, wherein at least one ring is aromatic, and may be unsubstituted or substituted.
  • aryl elements include phenyl, p- toluenyl (4-methylphenyl), naphthyl, tetrahydro-naphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl.
  • the aryl substituent is bicyclic and one ring is non- aromatic, it is understood that attachment is via the aromatic ring.
  • halogen refers to F, Cl, Br, and I.
  • haloalkyl means an alkyl group that is substituted with one or more fluorine, chlorine, bromine or iodine atoms. Examples of such haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl, chloromethyl, chlorofluoromethyl and trichloromethyl groups.
  • alkoxy means an -O-alkyl group in which alkyl is defined herein. Preferably the alkoxy is a C 1 -C 6 alkoxy.
  • substitution refers to a functional group as described above in which one or more bonds to a hydrogen atom contained therein are replaced by a bond to non-hydrogen or non-carbon atoms, provided that normal valencies are maintained and that the substitution results in a stable compound.
  • Substituted groups also include groups in which one or more bonds to a carbon(s) or hydrogen(s) atom are replaced by one or more bonds, including double or triple bonds, to a heteroatom.
  • substituent groups include the functional groups described herein, and halogens (i.e., F, Cl, Br, and I); alkyl groups, such as methyl, ethyl, n-propyl, and trifluorom ethyl; hydroxyl; alkoxy groups, such as methoxy, ethoxy, n-propoxy, and isopropoxy; aryloxy groups, such as phenoxy; arylalkyloxy.
  • the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally. By independently substituted, it is meant that the (two or more) substituents can be the same or different.
  • substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure result.
  • the compounds of the subject invention may have spontaneous tautomeric forms. In cases wherein compounds may exist in tautomeric forms, such as keto-enol tautomers, each tautomeric form is contemplated as being included within this invention whether existing in equilibrium or predominantly in one form.
  • This invention also provides isotopic variants of the compounds disclosed herein, including wherein the isotopic atom is 2 H and/or wherein the isotopic atom 13 C. Accordingly, in the compounds provided herein hydrogen can be enriched in the deuterium isotope. It is to be understood that the invention encompasses all such isotopic forms. In the compound structures depicted herein, hydrogen atoms are not shown for carbon atoms having less than four bonds to non-hydrogen atoms. However, it is understood that enough hydrogen atoms exist on said carbon atoms to satisfy the octet rule.
  • each stereogenic carbon may be of the R or S configuration. It is to be understood accordingly that the isomers arising from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of this invention, unless indicated otherwise. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis.
  • the compounds of the present invention include all hydrates, solvates, and complexes of the compounds used by this invention.
  • the compounds used in the method of the present invention may be in a salt form.
  • a “salt” is a salt of the instant compounds which has been modified by making acid or base salts of the compounds.
  • the salt is pharmaceutically acceptable.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as phenols.
  • the salts can be made using an organic or inorganic acid.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like.
  • compositions of Matter The presently disclosed subject matter relates to compositions comprising USP1 inhibitors and methods of using the same.
  • the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof:
  • the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein R 1 is selected from C 3 -C 8 cycloalkyl ring, C6-C10 aryl, or 4-, 5-, 6-, or 7- membered heterocyclyl ring, and C6-C10 aryl fused with 3-8 membered heterocyclic group; wherein R 1 is optionally substituted with one or more groups selected from -OH, -COOH, -NH 2 , -CN, halogen, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, -OCD 3 , C 1-6 haloalkoxy, C
  • the present disclosure is directed to a compound of formula (I) or a pharmaceutically acceptable salt thereof: wherein R 2 is selected from: , , , and ; R3 is selected from H, D, -OH, -COOH, -NH 2 , -CN, halogen, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and C 1-6 hydroxyalkyl; Z, U, V, W, P, Q, S, and T are independently selected from C, O, N, and S; wherein Z, U, V, W, P, Q, S, and T are optionally substituted with one or more groups selected from -OH, -COOH, -NH 2 , -CN, -CD(CD 3 ) 2 , halogen, C 1- 6 alkyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy
  • the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein R 2 is , Z is selected from C, O, N, and S; and R3 is selected from H, D, -OH, -COOH, -NH2, -CN, halogen, C1- 6 alkyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and C 1-6 hydroxyalkyl; wherein the phenyl ring is optionally substituted with one or more groups selected from - OH, -COOH, -NH2, -CN, halogen, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, and C3-C8 cycloalkyl ring.
  • the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein R 2 is selected from: , , and .
  • the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein R 2 is , the 5 and 6 membered ring are saturated or unsaturated;
  • R3 is selected from H, D, -OH, -COOH, -NH2, -CN, halogen, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and C 1-6 hydroxyalkyl; and
  • Z, U, V, W, P, Q, S, and T are independently selected from C, O, N, and S, wherein Z, U, V, W, P, Q, S and T are optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, -
  • the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein R 2 is selected from: In certain embodiments, the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein R 2 is ,the 5- membered ring is saturated or unsaturated; R3 is selected from H, D, -OH, -COOH, -NH2, - CN, halogen, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and C 1-6 hydroxyalkyl; and Z, P, Q, and S are independently selected from C, O, N, and S, wherein Z, P, Q, and S are optionally substituted with one or more groups selected from -OH, - COOH, -NH2, -CN, halogen, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 hal
  • the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein R 2 is selected from: , , , and .
  • the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein R 2 is , and is saturated or unsaturated; Z, P, Q, and S are independently selected from C, O, N, and S, wherein Z, P, Q, and S are optionally substituted with one or more groups selected from - OH, -COOH, -NH2, -CN, halogen, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, and C 3 -C 8 cycloalkyl ring.
  • the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein R 2 is selected from: , , and . In certain embodiments, the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein X 1 is selected from C and N.
  • the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein X 2 is selected from C and N; wherein when X 2 is C, the said C is optionally substituted with hydrogen, halogen, -CN, - OR 4 , -SR 4 , -N(R5)2, C 1-6 alkyl, C 1-6 haloalkyl, wherein R 4 and R5 are independently selected from C 1-6 alkyl.
  • the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein ring A is selected from: , and .
  • the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein ring A is selected from: , , , , and .
  • the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein ring A is In certain embodiments, the present disclosure is directed to a compound of formula (I) or a pharmaceutically acceptable salt thereof: wherein the compound is selected from:
  • the present disclosure is directed to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein R3 is selected from , , and , wherein W is selected from N or C. In certain embodiments, the present disclosure is directed to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein R3 is selected from , , , , and . In certain embodiments, the present disclosure is directed to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein when R3a and R 2 form a bond to form a 5- or 6-membered heterocyclyl, R 3 is .
  • the present disclosure is directed to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein when R3a and R3b combine to form a bridge, R3 is .
  • the present disclosure is directed to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein R 4 is selected from , , , , , , , and , wherein U and Y are independently selected from C or N, and wherein when U is N, Y is C, and when U is C, Y is N or C; wherein R5, R6, and R7 are independently selected from -H, -OH, -COOH, -NH 2 , -CN, halogen, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C3-C8 cycloalkyl ring, and 4-, 5-,
  • the present disclosure is directed to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein when R3 is , R 1 is selected from:
  • the present disclosure is directed to a compound of formula (II) or a pharmaceutically acceptable salt thereof: wherein when R3 is , R 1 is In certain embodiments, the present disclosure is directed to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein when R3 is , R 1 is . In certain embodiments, the present disclosure is directed to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein when R3 is , R 1 is , In certain embodiments, the present disclosure is directed to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein when R3 is , R 1 is selected from and .
  • the present disclosure is directed to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein ring A is a 5- or 6- membered heterocyclyl ring comprising one to three heteroatoms selected from N, O, or S; wherein when ring A is a 5-membered heterocyclyl ring and contains one heteroatom, ring A is selected from where X’ and X” are C and where X’ and X” are C; wherein when ring A is where X’ and X” are C, R 4 is , and Z is O, R7 is selected from -H, -OH, -COOH, -NH2, -CN, halogen, C3-6 alkyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 4 -C 8 cycloalkyl ring, and 4-, 5-, or 6- membered heterocycl
  • the present disclosure is directed to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein Ring A is a 5- membered heterocyclyl ring comprising one to three heteroatoms selected from N, O, or S; wherein when ring A is a 5-membered heterocyclyl ring and contains one heteroatom, ring A is selected from where X’ and X” are C and where X’ and X” are C; wherein when ring A is where X’ and X” are C, R 4 is , and Z is O, R7 is selected from -H, -OH, -COOH, -NH 2 , -CN, halogen, C 3-6 alkyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C4-C8 cycloalkyl ring, and 4-, 5-, or 6- membered heterocyclyl ring compris
  • the present disclosure is directed to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein ring A is .
  • the present disclosure is directed to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein when ring A is where X’ and X” are C, the compound of formula (II) or a pharmaceutically acceptable salt thereof comprises one or more of: Z is substituted with R 1 a or -CH2R 1 a, R3a and R3b are halogen, R5, R6, or R7 is a 4-, 5-, or 6- membered heterocyclyl ring, R3 is , R 4 is , , or where U and Y are C, where U is C and Y is N, or R3 is where U is N and Y is C, or a combination thereof.
  • the present disclosure is directed to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein when ring A is where X’ and X” are C , the compound of formula (II) or a pharmaceutically acceptable salt thereof comprises a ring A substituted with a C2-C 6 alkenyl.
  • the present disclosure is directed to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein when ring A is where X’ is N and X” is C, the compound of formula (II) or a pharmaceutically acceptable salt thereof comprises one or more of: R3a and R 2 form a bond to form a 5- or 6-membered heterocyclyl, R and R combine to f 3a 3b orm a bridge, R3 is , R 4 is , , or , R5, R6, or R7 a 4-, 5-, or 6- membered heterocyclyl ring, R3c forms a bond with R5 to form a 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12- membered heterocyclyl or C5-C12 cycloalkyl, or a combination thereof.
  • the present disclosure is directed to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein the compound is selected from:
  • the substituted purine was added (1.0 equiv.) and the reaction was heated at 50-100 °C for 1 ⁇ 16 h.
  • the reactions were concentrated under reduced pressure or extracted with EtOAc then washed with water, brine, dried over anhydrous sodium or magnesium sulfate, filtered, and concentrated under reduced pressure.
  • Step 2 Preparation of 1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)-N-methyl-methanamine•HCl.
  • Intermediate E To a stirred solution of 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)benzaldehyde (1.70 g, 6.02 mmol) and methylamine hydrochloride (0.810 g, 12.0 mmol) in MeOH (25.0 mL) at 0 °C and stirred for 30 min before adding sodium cyanoborohydride (1.14 g, 18.1 mmol).
  • the resulting reaction mixture was stirred at 23 °C for 16 h. After completion, the reaction mixture was quenched with cold water (25 ml) and then the MeOH was concentrated under reduced pressure. The material was extracted with EtOAc (50 mL x 2). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was dissolved in 4 M HCl in dioxane (5.0 ml) and the resulting reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure.
  • reaction mixture was ⁇ quenched with saturated NH 4 Cl solution ⁇ (10 ⁇ mL) and extracted with EtOAc ⁇ (2 ⁇ x 50 ⁇ mL). ⁇ The combined organic layer was washed with water (20 ⁇ mL), brine (20 ⁇ mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was dissolved in 4M hydrochloric acid solution in dioxane (10 mL). The mixture was stirred at 25 °C ⁇ for 1 h and ⁇ then concentrated under reduced pressure. Subsequently diethyl ether (5 mL) was added to the residue and the precipitated solid was filtered.
  • Triethylamine (2.50 mL, 18.2 mmol) was added followed by 4- dimethylaminopyridine (0.0740 g, 0.600 mmol) to the reaction mixture. Then, di-tert-butyl dicarbonate (1.45 mL, 6.66 mmol) was added, and the mixture was stirred at 25 °C for 4 h. After completion of the reaction, the mixture was diluted with cold water (10 mL) and extracted with EtOAc (2 x 25 mL). The combined organic layer was washed with water (25 mL), brine (25 mL), dried over anhydrous sodium sulfate, and filtered.
  • Step 3 Preparation of 1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3- methylphenyl)-N-methylmethanamine•TFA.
  • Intermediate H A stirred solution of tert-butyl (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)-3-methylbenzyl)carbamate (1.12 g, 2.81 mmol) in dichloromethane (23.0 mL) was treated with trifluoroacetic acid (0.400 g, 5.63 mmol) at 0 °C.
  • reaction mixture was concentrated under reduce pressure and the residue was dissolved in EtOAc (30 mL) and washed with water (10 mL), brine (5 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure.
  • the crude product was purified by flash chromatography (silica gel, 20–25% EtOAc in petroleum ether) to afford (4-(1-isopropyl-4-(trifluoromethyl)-1H- imidazol-2-yl)phenyl)methanethiol (30.0 mg) as a white solid.
  • LCMS observed m/z 301.3 [M+H] + .
  • Step 2 Preparation of 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cubane- 1-carboxamide.
  • Intermediate L.2 To a stirred solution of 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)cubane-1- carboxamide (4.50 g, 16.0 mmol) in N,N-dimethylformamide (50.0 mL) stirring at 0 °C were added Cs2CO3 (7.82 g, 24.0 mmol) and 2-iodopropane (3.26 g, 19.2 mmol). The reaction mixture was warmed to 60 °C and stirred for 12 h.
  • Step 3 Preparation of tert-butyl 2-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol- 2-yl)phenyl)-pyrrolidine-1-carboxylate.
  • Tetrakis(triphenylphosphine)palladium(0) (346 mg, 0.300 mmol) was added to the reaction and the mixture was heated at 150 °C for 30 minutes in a microwave reactor.
  • the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layer was washed with water (10 mL), brine (10 mL), and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure.
  • the reaction mixture was purged with nitrogen gas for 20 minutes, followed by the addition of palladium(II) acetate (0.310 g, 1.38 mmol) and cataXCium-A (0.990 g, 2.77 mmol).
  • the reaction mixture was then heated at 105 °C for 16 h in a sealed tube.
  • the reaction was filtered through a celite bed and washed with EtOAc (100 mL). The filtrate was further washed with water (50 mL) and brine (30 mL), dried over anhydrous sodium sulfate, and filtered.
  • the filtrate was concentrated under reduced pressure.
  • Step 3 Preparation of tert-butyl ((5-(4-(trifluoromethyl)-1H-imidazol-2-yl)pyrazin- 2-yl)methyl)carbamate.
  • Intermediate V.3 A stirred solution of 3,3-dibromo-1,1,1-trifluoropropan-2-one (2.73 g, 10.1 mmol) in water (50.0 mL) was prepared at 0 °C. Anhydrous sodium acetate (0.830 g, 10.1 mmol) was then added to the solution, and the mixture was stirred at 100 °C for 1 h.
  • Step 5 Preparation of (5-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)pyrazin-2-yl)methanamine•HCl.
  • Intermediate V A stirred solution of tert-butyl ((5-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)pyrazin-2-yl)methyl)carbamate (1.50 g, 3.89 mmol) in dichloromethane (15.0 mL) was treated with a 4.0 M solution of hydrochloric acid in dioxane (2.00 mL, 8.00 mmol) at 0 °C.
  • reaction mixture was then stirred at room temperature for 2 h. After completion, the reaction mixture was concentrated under reduced pressure. The residue was subsequently triturated with pentane (5 mL) to afford (5-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)pyrazin-2-yl)methanamine•HCl (1.01 g) as an off-white solid.
  • Step 2 Preparation of 4-(5-methoxy-3-(trifluoromethyl)-1H-pyrazol-1- yl)benzonitrile.
  • Intermediate X.2 To the stirred solution of 4-(5-hydroxy-3-(trifluoromethyl)-1H-pyrazol-1- yl)benzonitrile (3.0 g, 12 mmol) in N,N-dimethylformamide (30 mL) was added sodium hydride (0.28 g dispersion in mineral oil, 12 mmol) at 0 °C and the mixture was stirred for 10 min. Iodomethane (0.89 mL, 14 mmol) was added and the reaction was warmed to 23 °C and stirred for 16 h.
  • Step 3 Preparation of (4-(5-methoxy-3-(trifluoromethyl)-1H-pyrazol-1- yl)phenyl)-methanamine.
  • Intermediate X To a stirred solution of 4-(5-methoxy-3-(trifluoromethyl)-1H-pyrazol-1- yl)benzonitrile (5.3 g, 20 mmol) in THF (60 mL) was added LiAlH 4 (15 mL, 2.0 M in THF, 24 mmol) at 0 oC. The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was quenched with saturated ammonium chloride solution (100 mL) and extracted with EtOAc (100 mL x 3).
  • reaction mixture was stirred at 25 °C for 12 h in presence of air. Upon completion of reaction, the reaction mixture was filtered through celite and diluted with cold water (20 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layer was washed with brine (10 mL), dried over Anhydrous sodium sulfate, filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, 20–30% EtOAc in petroleum ether) to afford tert-butyl (4-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)benzyl)carbamate (0.25 g) as an off-white solid.
  • Step 2 Preparation of (4-(4-methyl-1H-1,2,3-triazol-1-yl)phenyl)methanamine Intermediate AQ
  • 4-(5-methyl-1H-1,2,3-triazol-1-yl)benzonitrile 110 mg, 0.597 mmol
  • lithium aluminium hydride 1.0 M in THF 1.8 ⁇ mL, 1.79 ⁇ mmol
  • Step 2 Preparation of 4-(1-isopropyl-3-(trifluoromethyl)-1H-1,2,4-triazol-5- yl)benzonitrile
  • Intermediate BA.2 To a stirred solution of 5-bromo-1-isopropyl-3-(trifluoromethyl)-1H-1,2,4-triazole (mixture of two regio-isomers) (800 mg, 3.10 mmol) in 1,4-dioxane (8 mL) and water (2 mL), (4-cyanophenyl) boronic acid (683 mg, 4.65 mmol) followed by potassium carbonate (1.28 g, 9.3 mmol) were added, and the mixture was purged with nitrogen gas for 30 min.
  • Tetrakis(triphenylphosphine)palladium(0) (358 mg, 0.31 mmol) was added to the reaction mixture and stirred at 110 °C for 16 h. After completion, the reaction mixture was diluted with water (2 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • Step 3 Preparation of (4-(1-isopropyl-3-(trifluoromethyl)-1H-1,2,4-triazol-5- yl)phenyl)methanamine Intermediate BA
  • 4-(1-isopropyl-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl) benzonitrile 800 mg, 2.85 mmol
  • LiAlH 4 powder 325 mg, 8.56 mmol
  • the reaction mixture was quenched with saturated NH4Cl solution (30 mL) and extracted with EtOAc (2 x 50 mL).
  • Step 2 Preparation of 4-(5-(prop-1-en-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1- yl)benzonitrile Intermediate BF.2
  • 4-(5-bromo-3-(trifluoromethyl)-1H-pyrazol-1- yl)benzonitrile (2.5 g, 7.91 mmol) in 1,4-dioxane (50.0 mL) and water (5.0 mL)
  • 4,4,5,5- tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (2.66 g, 15.82 mmol) and potassium carbonate (3.3 g, 23.73 mmol) were added.
  • reaction mixture was purged with nitrogen gas for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.91 g, 0.79 mmol) was then added, and the mixture was stirred at 110 °C for 16 hours. Upon completion, the reaction was quenched with cold water (25 mL) and extracted with EtOAc (2 ⁇ 50 mL). The combined organic layer was washed with water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure.
  • Step 3 Preparation of (4-(5-isopropyl-3-(trifluoromethyl)-1H-pyrazol-1- yl)phenyl)methanamine Intermediate BF
  • 4-(5-(prop-1-en-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1- yl)benzonitrile (1.8 g, 6.5 mmol) in EtOAc (50 mL)
  • palladium on carbon 50% wet basis, 1.8 g
  • platinum(IV) oxide 0.2 g
  • acetic acid 0.5 mL
  • Step 2 Preparation of 4-(1-allyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3- bromobenzonitrile Intermediate BH.2
  • dimethylformamide 9.04 mL, 117 mmol
  • dipotassium carbonate 1.25 g, 2 eq., 9.04 mmol
  • 3-bromopropene 586 ⁇ L, 1.5 eq., 6.78 mmol
  • Step 3 Preparation of 4-(1-allyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3- vinylbenzonitrile.
  • Intermediate BH.3 To a suspension of 4-(1-allyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3- bromobenzonitrile (356 mg, 1 mmol), Cs2CO3 (977 mg, 3 eq., 3 mmol), and 4,4,5,5- tetramethyl-2-vinyl-1,3,2-dioxaborolane (509 ⁇ L, 3 eq., 3 mmol) in 1,4-dioxane (4 mL, 46.9 mmol) and water (1 mL, 20 eq., 20 mmol) was added dichloro-palladamethane— dichloromethane—iron—1 ⁇ 3,2 ⁇ 3,3 ⁇ 3,4 ⁇ 3,5 ⁇ 3-cyclopentyldiphenylphosphine (1/
  • the vial was sealed and heated at 85 C for 16 h. The reaction was not complete at this time. An additional 2.0 equiv of the vinyl borane was added followed by Pd(dppf)Cl2 (100 mg) and the reaction was heated to 100 C for 24 h. At this point the starting material was consumed. The reaction was diluted with water (20 mL) and extracted with dichloromethane (2 x 20 mL). The combined organics were dried over MgSO 4 , filtered and concentrated under reduced pressure.
  • Step 5 Preparation of (2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2- a]azepin-9-yl)methanamine.
  • Intermediate BH To a solution of 4-(trifluoromethyl)-3,6-diazatricyclo[8.4.0.02,6]tetradeca- 1(14),2,4,8,10,12-hexaene-12-carbonitrile (473 mg, 1.72 mmol) in tetrahydrofuran (10 mL, 123 mmol) and MeOH (10 mL, 247 mmol) at 0 °C was added nickel dichloride (81.8 mg, 0.2 eq., 344 ⁇ mol) followed by NaBH 4 (309 mg, 3 eq., 5.16 mmol).
  • Step 2 Preparation of tert-butyl ((4-(4-(trifluoromethyl)-1H-imidazol-2-yl)-2- oxabicyclo[2.2.2]octan-1-yl)methyl)carbamate Intermediate BI.2
  • 3,3-dibromo-1,1,1-trifluoro-2-propanone 206 ⁇ L, 1.1 eq., 1.67 mmol
  • sodium acetate 138 mg, 1.1 eq., 1.68 mmol
  • Step 3 Preparation of tert-butyl ((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol- 2-yl)-2-oxabicyclo[2.2.2]octan-1-yl)methyl)carbamate Intermediate BI.3 To a suspension of tert-butyl ( ⁇ 4-[4-(trifluoromethyl)-2-imidazolyl]-2- oxabicyclo[2.2.2]oct-1-yl ⁇ methyl)carbamate (563 mg, 1.5 mmol) and dicaesium carbonate (1.47 g, 3 eq., 4.5 mmol) in acetonitrile (6 mL, 115 mmol) stirring at 23 °C was added 2- iodopropane (0.6 mL, 4 eq., 6
  • Step 4 Preparation of ( ⁇ 4-[1-isopropyl-4-(trifluoromethyl)-2-imidazolyl]-2- oxabicyclo[2.2.2]oct-1-yl ⁇ methyl)amine—hydrogen chloride (1/1) Intermediate BI To a solution of tert-butyl ( ⁇ 4-[1-isopropyl-4-(trifluoromethyl)-2-imidazolyl]-2- oxabicyclo[2.2.2]oct-1-yl ⁇ methyl)carbamate (201 mg, 481 ⁇ mol) in 1,4-dioxane (481 ⁇ L, 5.64 mmol) stirring at 23 °C was added HCl in 1,4-dioxane (4M, 3.0 mmol, 3.0 mL and the reaction was stirred at 23 °C for 1 h.
  • Step 2 Preparation of (4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1- yl)phenyl)methanol Intermediate BJ
  • methyl 4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1- yl)benzoate 6.5 g, 22.87 mmol
  • diisobutylaluminium hydride 1M solution in hexane (91 mL, 91.47 mmol) at 0° C.
  • the reaction mixture was stirred at 25 °C for 2 h and the progress of the reaction was monitored by TLC and LCMS.
  • reaction mixture was quenched with saturated ammonium chloride solution (200 mL), diluted with EtOAc (300 mL), stirred for 15 min and filtered through celite. The organic layer was partitioned and the aqueous layer was extracted with EtOAc (200 mL). The combined organic layer was washed with brine (100 ⁇ mL), ⁇ dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • reaction mixture was filtered through celite and diluted with cold water (100 mL), then extracted with EtOAc (2 ⁇ 50 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • Step 2 Preparation of tert-butyl ((2-(trifluoromethyl)-6,7-dihydro-5H- benzo[b]imidazo[2,1-d][1,5]oxazocin-10-yl)methyl)carbamate Intermediate BN.2
  • 2-(trifluoromethyl)-6,7-dihydro-5H-benzo[b]imidazo[2,1- d][1,5]oxazocine-10-carbonitrile (1.8 g, 6.14 ⁇ mmol)
  • EtOAc (30 mL) and MeOH (30 mL) was added palladium on carbon (50% wet basis) (1.8 g) and di-tert-butyl dicarbonate (8.03 ⁇ g, 36.83 ⁇ mmol) at 25 °C.
  • Step 3 Preparation of (2-(trifluoromethyl)-6,7-dihydro-5H-benzo[b]imidazo[2,1- d][1,5]oxazocin-10-yl)methanamine Intermediate BN
  • tert-butyl ((2-(trifluoromethyl)-6,7-dihydro-5H- benzo[b]imidazo[2,1-d][1,5]oxazocin-10-yl)methyl)carbamate (1.0 g, 2.156 mmol) in ⁇ dichloromethane (10 mL) was added ⁇ TFA (1.0 mL) at 0 °C and reaction mixture was allowed to stir at 25 °C for 4 h.
  • Step 2 Preparation of (Z)-2-(trifluoromethyl)-5,8-dihydrobenzo[c]imidazo[1,2- a]azocine-10-carbonitrile Intermediate BQ.2
  • Step 3 Preparation of tert-butyl ((2-(trifluoromethyl)-5,6,7,8- tetrahydrobenzo[c]imidazo[1,2-a]azocin-10-yl)methyl)carbamate Intermediate BQ.3
  • Step 4 Preparation of (2-(trifluoromethyl)-5,6,7,8-tetrahydrobenzo[c]imidazo[1,2- a]azocin-10-yl)methanamine
  • Intermediate BQ A stirred solution of tert-butyl ((2-(trifluoromethyl)-5,6,7,8- tetrahydrobenzo[c]imidazo[1,2-a]azocin-10-yl)methyl)carbamate (0.12 g, 0.30 mmol) in dichloromethane (3 mL) was cooled to 0 °C, and TFA (1.5 mL) was added. The reaction mixture was allowed to stir at room temperature for 2 hours. Upon completion, the reaction mixture was concentrated under reduced pressure.
  • Step 2 Preparation of methyl 5-cyano-2-(1-(tetrahydro-2H-pyran-2-yl)-4- (trifluoromethyl)-1H-imidazol-2-yl)benzoate Intermediate BR.2
  • p-toluenesulfonic acid monohydrate (0.38 g, 2.03 mmol) followed by 3,4-dihydropyran (1.79 mL, 20.32 mmol) were added at room temperature and the reaction mixture was stirred at 80 °C for 12 h.
  • Step 3 Preparation of 3-(hydroxymethyl)-4-(1-(tetrahydro-2H-pyran-2-yl)-4- (trifluoromethyl)-1H-imidazol-2-yl)benzonitrile
  • Intermediate BR.3 To a stirred solution of methyl 5-cyano-2-(1-(tetrahydro-2H-pyran-2-yl)-4- (trifluoromethyl)-1H-imidazol-2-yl)benzoate (2.5 g, 6.59 mmol) in tetrahydrofuran (25 mL), MeOH (25 mL) was added NaBH4 (0.997 g, 26.36 mmol) at 0 °C.
  • reaction mixture was stirred at 50 °C for 6 h. On completion, the reaction mixture ⁇ was diluted with ice cold water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layer was dried over anhydrous sodium sulfate ⁇ and concentrated under reduced pressure.
  • the crude product was purified by flash chromatography (Davisil silica-gel) using 40% EtOAc in petroleum ether as an eluent to afford 3-(hydroxymethyl)-4-(1-(tetrahydro-2H-pyran-2- yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzonitrile (2.3 g) as a pale yellow gum.
  • Step 4 Preparation of 3-((2-((tert-butyldimethylsilyl)oxy)ethoxy)methyl)-4-(1- (tetrahydro-2H-pyran-2-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzonitrile
  • Intermediate BR.4 To a stirred solution of 3-(hydroxymethyl)-4-(1-(tetrahydro-2H-pyran-2-yl)-4- (trifluoromethyl)-1H-imidazol-2-yl)benzonitrile (450 mg, 1.28 mmol) inTHF (5 mL), was added sodium hydride (60%, dispersion in paraffin liquid) (0.12 g, 5.12 mmol) ⁇ at 0°C.
  • Step 5 Preparation of 3-((2-hydroxyethoxy)methyl)-4-(4-(trifluoromethyl)-1H- imidazol-2-yl)benzonitrile
  • Intermediate BR.5 To a stirred solution of 3-((2-((tert-butyldimethylsilyl)oxy)ethoxy)methyl)-4-(1- (tetrahydro-2H-pyran-2-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzonitrile (2.0 g, 3.92 mmol) in dichloromethane ⁇ (10 ⁇ mL) was added TFA (4.0 mL) at 0°C and allowed to stirred at 25 °C for 4 h.
  • TFA 4.0 mL
  • Step 6 Preparation of 2-(trifluoromethyl)-5,6-dihydro-8H-benzo[f]imidazo[1,2- d][1,4]oxazocine-10-carbonitrile
  • Intermediate BR.6 To a stirred solution of 3-((2-hydroxyethoxy)methyl)-4-(4-(trifluoromethyl)-1H- imidazol-2-yl)benzonitrile (1.3 g, 4.17 mmol) in toluene (20 ⁇ mL) was added 2-(tributyl-l5- phosphaneylidene)acetonitrile (1.16 g, 4.82 mmol) at 25°C and allowed to stirred at 100 °C for 6 h.
  • Step 7 Preparation of tert-butyl ((2-(trifluoromethyl)-5,6-dihydro-8H- benzo[f]imidazo[1,2-d][1,4]oxazocin-10-yl)methyl)carbamate Intermediate BR.7
  • Step 8 Preparation of (2-(trifluoromethyl)-5,6-dihydro-8H-benzo[f]imidazo[1,2- d][1,4]oxazocin-10-yl)methanamine Intermediate BR To a stirred solution of ⁇ tert-butyl ((2-(trifluoromethyl)-5,6-dihydro-8H- benzo[f]imidazo[1,2-d][1,4]oxazocin-10-yl)methyl)carbamate (0.230 g, 0.579 mmol) in ⁇ dichloromethane (5 ⁇ mL) was added ⁇ TFA (0.5 mL) at 0 °C and allowed to stirred at 25 °C for 4 h.
  • ⁇ tert-butyl ((2-(trifluoromethyl)-5,6-dihydro-8H- benzo[f]imidazo[1,2-d][1,4]oxazocin-10-yl)methyl)carbamate (0.230 g,
  • Step 3 Preparation of tert-butyl ((6-oxo-2-(trifluoromethyl)-6,7-dihydro-5H- benzo[f]imidazo[1,2-d][1,4]diazepin-9-yl)methyl)carbamate
  • Intermediate BS.3 To a stirred solution of 6-oxo-2-(trifluoromethyl)-6,7-dihydro-5H- benzo[f]imidazo[1,2-d][1,4]diazepine-9-carbonitrile (0.3 g, 1.03 mmol) in a mixture of EtOAc (25 mL) and MeOH (25 mL), palladium on carbon (10%, wetted with approximately 55% water) (0.33 g, 3.08 mmol) and di-tert-butyl dicarbonate (0.71 mL, 3.08 mmol) were added.
  • Step 4 Preparation of 9-(aminomethyl)-2-(trifluoromethyl)-5H- benzo[f]imidazo[1,2-d][1,4]diazepin-6(7H)-one Intermediate BS To a stirred solution ⁇ of ⁇ tert-butyl ((6-oxo-2-(trifluoromethyl)-6,7-dihydro-5H- benzo[f]imidazo[1,2-d][1,4]diazepin-9-yl)methy (0.2 g, 0.51 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (0.155 mL, 2.02 mmol) at 0 °C and stirred at rt for 2 h.
  • reaction mixture was stirred at 25 °C for 16 hours. Upon completion, the reaction mixture was quenched with cold water (100 mL) and extracted with EtOAc (2 ⁇ 250 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure.
  • the crude product was purified by flash chromatography (Davisil silica gel, 25–30% EtOAc in petroleum ether) to afford 7-oxo-2- (trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepine-9-carbonitrile (1.1 g) as a pale brown solid.
  • Step 2 Preparation of tert-butyl ((7-hydroxy-2-(trifluoromethyl)-6,7-dihydro-5H- benzo[c]imidazo[1,2-a]azepin-9-yl)methyl)carbamate
  • Intermediate BT.2 A solution of 7-oxo-2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2- a]azepine-9-carbonitrile (1.3 g, 4.46 mmol) in a mixture of EtOAc (150 mL) and MeOH (150 mL) was stirred, and di-tert-butyl dicarbonate (2.05 mL, 8.93 mmol) was added, followed by 10% palladium on carbon (wet with approximately 55% water; 1.5 g).
  • the reaction mixture was stirred under hydrogen gas pressure (80 psi) in a Paar shaker at room temperature for 16 hours. Upon completion, the reaction mixture was filtered through a celite bed, which was then washed with THF (100 mL). The filtrate was concentrated under reduced pressure.
  • the crude product was purified by flash chromatography (Davisil silica gel, 75–80% EtOAc in petroleum ether) to afford tert-butyl ((7-hydroxy-2- (trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepin-9-yl)methyl)carbamate (0.80 g) as an off-white solid.
  • Step 3 Preparation of 9-(aminomethyl)-2-(trifluoromethyl)-6,7-dihydro-5H- benzo[c]imidazo[1,2-a]azepin-7-ol
  • Intermediate BT To a stirred solution of tert-butyl ((7-hydroxy-2-(trifluoromethyl)-6,7-dihydro-5H- benzo[c]imidazo[1,2-a]azepin-9-yl)methyl)carbamate (500 mg, 1.26 mmol) in dichloromethane (15 mL), trifluoroacetic acid (2.0 mL) was added at 0 °C.
  • reaction mixture was stirred at 100 °C for 16 hours. Upon completion, the reaction mixture was diluted with ice water (50 mL) and extracted with EtOAc (2 ⁇ 50 mL). The combined organic layers were washed with water (50 mL ⁇ 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the crude product was purified by flash chromatography (30–50% EtOAc/petroleum ether eluent) to afford 3-fluoro-4-(1-(2-(2-hydroxyethoxy)ethyl)-4-(trifluoromethyl)-1H-imidazol-2- yl)benzonitrile (1.1 g) as a pale yellow gum.
  • Step 2 Preparation of 2-(trifluoromethyl)-5,6,8,9-tetrahydrobenzo[i]imidazo[1,2- g][1,4,7]dioxazecine-12-carbonitrile Intermediate BW.2 To a stirred solution of 3-fluoro-4-(1-(2-(2-hydroxyethoxy)ethyl)-4- (trifluoromethyl)-1H-imidazol-2-yl)benzonitrile (0.9 g, 2.62 mmol) ⁇ in DMF (9 ⁇ mL) ⁇ was added ⁇ Cs2CO3 (1.7 ⁇ g, 5.24 ⁇ mmol) ⁇ and the reaction was heated at 100 °C for 6 h.
  • Step 3 Preparation of tert-butyl ((2-(trifluoromethyl)-5,6,8,9- tetrahydrobenzo[i]imidazo[1,2-g][1,4,7]dioxaqueln-12-yl)methyl)carbamate Intermediate BW.3
  • a stirred solution of 2-(trifluoromethyl)-5,6,8,9- tetrahydrobenzo[i]imidazo[1,2-g][1,4,7]dioxazecine-12-carbonitrile 0.5 g, 1.54 mmol
  • MeOH MeOH
  • EtOAc 10 mL
  • Step 4 Preparation of (2-(trifluoromethyl)-5,6,8,9-tetrahydrobenzo[i]imidazo[1,2- g][1,4,7]dioxazin-12-yl)methanamine Intermediate BW To a stirred solution of tert-butyl ((2-(trifluoromethyl)-5,6,8,9- tetrahydrobenzo[i]imidazo[1,2-g][1,4,7]dioxazecin-12-yl)methyl)carbamate (0.5 g, 1.17 mmol) in dichloromethane (10 mL) at 0 °C under an argon atmosphere, TFA (3 mL) was added.
  • Step 2 Preparation of tert-butyl ((4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1- yl)cyclohexyl)methyl)carbamate Intermediate BX.2
  • Cs 2 CO 3 (6.512 g, 19.98 mmol)
  • 4-(((tert- butoxycarbonyl)amino)methyl)cyclohexyl methanesulfonate (3.072 g, 9.99 ⁇ mmol) at 0 °C and ⁇ reaction was allowed to stir at ⁇ 80 °C for 16 h.
  • Step 2 Preparation of (1-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)piperidin-4-yl)methanamine Intermediate BY To a stirred solution of tert-butyl ((1-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol- 2-yl)piperidin-4-yl)methyl)carbamate (0.3 g, 0.77 mmol) in dichloromethane (10 mL), trifluoroacetic acid (2.0 mL) was added at 0 °C. The reaction mixture was then stirred from 0 °C to 25 °C for 2 hours.
  • Step 2 Preparation of tert-butyl (4-(5-(2-hydroxypropan-2-yl)-3-(trifluoromethyl)- 1H-pyrazol-1-yl)benzyl)carbamate Intermediate CB.2
  • ethyl 1-(4-(((tert-butoxycarbonyl) amino) methyl) phenyl)- 3-(trifluoromethyl)-1H-pyrazole-5-carboxylate 6.0 g, 41.3 mmol
  • tetrahydrofuran 80.0 mL
  • methylmagnesium bromide 1.4 M, 103 mL, 145 mmol
  • Step 3 Preparation of 2-(1-(4-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H- pyrazol-5-yl)propan-2-ol
  • Intermediate CB To a stirred solution of tert-butyl (4-(5-(2-hydroxypropan-2-yl)-3-(trifluoromethyl)- 1H-pyrazol-1-yl) benzyl) carbamate (3.3 g, 8.26 mmol) in dichloromethane (20 mL), was added trifluoroacetic acid (5 mL) at 0 °C under a nitrogen atmosphere. The reaction mixture was stirred at 25 °C for 2 hours.
  • XPhosPdG3 (0.033 g, 0.03 mmol) was added and reaction mixture was stirred at 90 °C for 16 h.
  • the reaction mixture was diluted with water (25 mL) and the product was extracted with ethyl acetate (2 x 50 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • Step 2 Preparation of (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)methan-d2-amine Intermediate CL
  • the title compound was prepared using a similar procedure to Intermediate BA, replacing 4-(1-isopropyl-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl) benzonitrile with 4-(1- isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl) benzamide and using LiAlD4 to reduce the carboxamide.
  • Step 2 Preparation of tert-butyl (3-bromo-4-(4-(trifluoromethyl)-1H-imidazol-2- yl)benzyl)carbamate Intermediate CN.2
  • a stirred solution of (3-bromo-4-(4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)methanamine (2 g, 6.2 mmol) in dichloromethane (20 mL) was cooled to 0 °C, and N,N-diisopropylethylamine (2.4 g, 18.7 mmol), 4-(dimethylamino)pyridine (0.076 g, 0.625 mmol), and di-tert-butyl dicarbonate (2.7 g, 12.4 mmol) were added sequentially.
  • the reaction mixture was stirred at room temperature for 16 hours. Upon completion, the reaction was diluted with water (100 mL) and extracted with EtOAc (2 ⁇ 100 mL). The combined organic layers were washed with ice-cold water (100 mL) and brine (100 mL), then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, 30– 50% EtOAc in petroleum ether) to afford tert-butyl (3-bromo-4-(4-(trifluoromethyl)-1H- imidazol-2-yl)benzyl)carbamate (1.5 g) as a white solid.
  • Step 3 Preparation of tert-butyl (3-(prop-1-en-2-yl)-4-(4-(trifluoromethyl)-1H- imidazol-2-yl)benzyl)carbamate Intermediate CN.3
  • tert-butyl (3-bromo-4-(4-(trifluoromethyl)-1H-imidazol-2- yl)benzyl)carbamate (1.5 g, 3.5 mmol) and potassium trifluoro(prop-1-en-2-yl)borate (2.6 g, 17.8 mmol) in 1,4-dioxane (20 mL) and water (5 mL) was added K3PO4 (2.273 g, 10.708 mmol), and the reaction mixture was purged with argon gas for 15 minutes.
  • XPhosPd(G2) (0.2 g, 0.35 mmol) was introduced, and the reaction mixture was stirred at 70 °C for 2 hours. Upon completion, the reaction was diluted with water (200 mL) and extracted with EtOAc (3 ⁇ 100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, 70% EtOAc in petroleum ether) to afford tert-butyl (3-(prop-1- en-2-yl)-4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)carbamate (1.5 g) as an off-white solid.
  • Step 4 Preparation of tert-butyl (3-(1-hydroxypropan-2-yl)-4-(4-(trifluoromethyl)- 1H-imidazol-2-yl)benzyl)carbamate Intermediate CN.4 A stirred solution of tert-butyl (3-(prop-1-en-2-yl)-4-(4-(trifluoromethyl)-1H- imidazol-2-yl)benzyl)carbamate (1 g, 2.6 mmol) in THF (10 mL) was cooled to 0 °C, and 1 M borane in THF (10 mL, 7.86 mmol) was added.
  • reaction mixture was stirred at 0 °C for 1 hour. After 1 hour, hydrogen peroxide (35% in water) (0.76 mL, 7.8 mmol) was added, followed by potassium carbonate (0.725 g, 5.24 mmol), and the mixture was stirred at room temperature for 1 hour. Upon completion, the reaction was quenched with water (100 mL) and extracted with EtOAc (3 ⁇ 50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • Step 5 Preparation of tert-butyl ((6-methyl-2-(trifluoromethyl)-5,6- dihydroimidazo[2,1-a]isoquinolin-8-yl)methyl)carbamate Intermediate CN.5
  • reaction mixture was stirred at 100 °C for 16 hours. Upon completion, the reaction was quenched with water (100 mL) and extracted with EtOAc (3 ⁇ 50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • the crude product was purified by flash chromatography (silica gel, 70% EtOAc in petroleum ether) to afford tert-butyl ((6-methyl-2-(trifluoromethyl)-5,6-dihydroimidazo[2,1- a]isoquinolin-8-yl)methyl)carbamate (0.6 g) as an off-white solid (two inseparable regio- isomers which were carried forward and separated at the final step).
  • Step 2 Preparation of 6-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-2,3- dihydrobenzofuran-3-amine Intermediate CP
  • TFA 0.5 mL
  • Step 2 Preparation of 1-(tetrahydro-2H-pyran-4-yl)-4-(trifluoromethyl)-1H- imidazole Intermediate CQ.2
  • a stirred solution of ⁇ 1-(3,6-dihydro-2H-pyran-4-yl)-4-(trifluoromethyl)-1H- imidazole (2.2 g, 10 ⁇ mmol) ⁇ in EtOAc (22 ⁇ mL) was added palladium hydroxide, 20% on carbon (wet) (3.11 ⁇ g, 22.1 ⁇ mmol) at room temperature under nitrogen atmosphere and reaction mixture was allowed to shake in parr shaker under 50 psi of hydrogen pressure at rt ⁇ for 16 h. Progress of reaction was monitored by TLC and LCMS.
  • Step 3 Preparation of 2-bromo-1-(tetrahydro-2H-pyran-4-yl)-4-(trifluoromethyl)- 1H-imidazole Intermediate CQ
  • 1-(tetrahydro-2H-pyran-4-yl)-4-(trifluoromethyl)-1H- imidazole (2 g, 9.08 mmol)
  • n-butyl lithium, 1.6 M in hexane (0.75 g, 11.8 mmol
  • Step 2 Preparation of (4-(1-(tetrahydro-2H-pyran-4-yl)-4-(trifluoromethyl)-1H- imidazol-2-yl)phenyl)methanamine Intermediate CR
  • tert-butyl (4-(1-(tetrahydro-2H-pyran-4-yl)-4- (trifluoromethyl)-1H-imidazol-2-yl)benzyl)carbamate 0.085 g, 0.20 mmol
  • trifluoroacetic acid 0.06 mL, 3.99 mmol
  • Step 2 Preparation of tert-butyl (4-(1-cyclopropyl-4-(trifluoromethyl)-1H- imidazol-2-yl)benzyl)carbamate Intermediate CU.2
  • the stirred solution of 4-(1-cyclopropyl-4-(trifluoromethyl)-1H- imidazol-2-yl)benzonitrile 9 g, 32.462 mmol
  • EtOAc 150 mL
  • MeOH 150 mL
  • Step 3 Preparation of (4-(1-cyclopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)methanamine Intermediate CU
  • tert-butyl (4-(1-cyclopropyl-4-(trifluoromethyl)-1H- imidazol-2-yl)benzyl)carbamate 8 g, 20.975 mmol
  • dichloromethane 50 mL
  • Trifluoroacetic acid 6 mL, 209.754 mmol
  • Step 2 Preparation of tert-butyl 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4- (1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)-5,6-dihydro-7H- pyrrolo[2,3-d]pyrimidine-7-carboxylate.
  • reaction mixture was degassed with nitrogen gas for 10 minutes before adding tetrakis(triphenylphosphine)palladium(0) (15.9 mg, 0.014 mmol).
  • the reaction mixture was further degassed with nitrogen gas for additional 5 minutes and stirred under microwave at 100 °C for 1.5 h.
  • the reaction mixture was quenched with water (20 mL) and extracted with EtOAc (20 mL x 3).
  • the combined organic layer was washed with water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate and filtered.
  • Step 3 Preparation of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-methyl- 4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4- amine.
  • Step 2 Preparation of tert-butyl 2-(4-cyclopropyl-1-ethyl-1H-pyrazol-5-yl)-4-((4- (1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)-5,7-dihydro-6H- pyrrolo[3,4-d]pyrimidine-6-carboxylate.
  • Step 3 Preparation of 2-(4-cyclopropyl-1-ethyl-1H-pyrazol-5-yl)-N-(4-(1-methyl- 4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4- amine.
  • Step 4 Preparation of 2-(2-(4-cyclopropyl-1-ethyl-1H-pyrazol-5-yl)-4-((4-(1- methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4- d]pyrimidin-6-yl)acetonitrile.
  • reaction Upon completion, the reaction was diluted with water (20 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layer was washed with water (10 mL), brine (10 mL), dried over anhydrous sodium sulfate, and filtered.
  • reaction Upon completion, the reaction was diluted with water (20 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layer was washed with water (10 mL), brine (10 mL), dried over anhydrous sodium sulfate, and filtered.
  • Step 2 Preparation of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1- isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)imidazo[2,1-f][1,2,4]triazin-4- amine.
  • Compound 14 The title compound was prepared using a similar procedure as Compound 12, replacing (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanamine and 2,4-dichloro-imidazo[2,1-f][1,2,4]triazine with (4-(5-methyl-3-(trifluoromethyl)-1H- pyrazol-1-yl)phenyl)-methanamine•HCl (Intermediate Y) and 5,7-dichlorothiazolo[5,4- d]pyrimidine.
  • Step 3 Preparation of N-cyclopropyl-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)- N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7H-purin-6-amine.
  • reaction mixture was diluted with a saturated sodium bicarbonate solution (5 mL) and extracted with dichloromethane (2 X 5 mL). The combined organic layer was washed with brine (2 X 5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • Step 2 Preparation of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6-(2-(4-(1- isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)pyrrolidin-1-yl)-7H-purine.
  • Compound 37 The title compound was prepared using a similar procedure as Compound 32, replacing 1-isopropyl-2-(4-(pyrrolidin-2-yl)phenyl)-4-(trifluoromethyl)-1H-imidazole with (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3-methylphenyl)- methanamine•HCl (Intermediate G).
  • Step 3 Preparation of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6-((4-(1- isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)-7H-purine.
  • Step 5 Preparation of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8,9-dimethyl-6- (methylsulfonyl)-9H-purine.
  • Compound 47.5 To a mixture of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8,9-dimethyl-6- (methylthio)-9H-purine (144 mg, 0.421 mmol) in dichloromethane (5.00 mL) was added 3- chloroperoxybenzoic acid (181 mg, 1.05 mmol) at 0°C and the resulting mixture was stirred at 0 °C for 4 hours.
  • Step 6 Preparation 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl- 4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-N,8,9-trimethyl-9H-purin-6-amine.
  • Step 2 Preparation 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl- 4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-N,8-dimethyl-7-(tetrahydro-2H-pyran-2-yl)- 7H-purin-6-amine.
  • Step 3 Preparation of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1- isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-N,8-dimethyl-7H-purin-6-amine.
  • Step 2 Preparation of N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)benzyl)-2-(2-isopropylphenyl)-7-(tetrahydro-2H-pyran-2-yl)-7H-purin-6-amine.
  • the reaction mixture was degassed with nitrogen gas for 10 minutes before adding tetrakis(triphenylphosphine)palladium(0) (78 mg, 0.07 mmol).
  • the reaction mixture was degassed with nitrogen gas for additional 5 minutes and then stirred at 100 °C for 2 h under microwave irradiation.
  • the reaction mixture was filtered through celite bed and the bed was thoroughly washed with EtOAc (50 mL).
  • the combined organic layer was washed with water (5 mL), brine (5 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure.
  • Step 3 Preparation of N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)benzyl)-2-(2-isopropylphenyl)-7H-purin-6-amine.
  • Step 2 Preparation of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-4-ol.
  • Compound 56.2 To a stirred solution of 4-cyclopropyl-6-methoxypyrimidine-5-carboximidamide (1.00 g, 5.20 mmol) and ethyl 5-ethoxy-3,4-dihydro-2H-pyrrole-4-carboxylate (2.89 g, 15.6 mmol) in MeOH (10 mL) was added sodium hydride (0.15 g, 6.24 mmol) at 0 °C and the reaction mixture was stirred for 10 min.
  • the resulting reaction mixture was stirred at 23 °C for 2 h. Upon completion, the mixture was diluted with ice-cold water (50 mL) and extracted with EtOAc (3 x 30 mL). The combined organic phases were washed with water (30 mL), brine (30 mL), dried over anhydrous sodium sulfate, and filtered.
  • Step 4 Preparation of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-methyl- 4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)-5,6-dihydro-7H-pyrrolo[2,3- d]pyrimidine-7-carbonitrile.
  • Step 2 Preparation of N-cyclobutyl-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N- (4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7H-purin-6-amine.
  • the vial was degassed via vacuum/N2 backfill (5x), sealed, and heated in the uW at 100 °C for 4 h.
  • the reaction was complete by LCMS.
  • the mixture was diluted with water (5 mL) and extracted with dichloromethane (2 x 5 mL). The combined organics were dried over MgSO4, filtered and concentrated to afford the crude product as a brown solid.
  • the solid was dissolved in trifluoroacetic acid (2 mL) and stirred for 2h at which time the reaction was complete by LCMS.
  • the reaction was concentrated and The crude product was purified via preparatory HPLC (10–75% MeCN/H2O w/ 0.1% FA) to afford the product as a white solid.
  • Compound 110 The title compound was prepared using a similar procedure as Compound 109, replacing 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)pyridine with 1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1H-pyrazole.
  • Compound 140 The title compound was prepared using a similar procedure as Compound 12, replacing (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanamine with (2-fluoro-4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanamine (Intermediate J).
  • Compound 150 The title compound was prepared using a similar procedure as Compound 12, replacing (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanamine with (4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)methanamine (Intermediate BX).

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Abstract

La présente invention concerne des compositions comprenant des inhibiteurs de protéase 1 spécifique de l'ubiquitine (USP1) et leurs méthodes d'utilisation.
PCT/US2024/060229 2023-12-15 2024-12-13 Compositions comprenant des inhibiteurs d'usp1 et leurs méthodes d'utilisation Pending WO2025129135A2 (fr)

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WO2006044762A2 (fr) * 2004-10-15 2006-04-27 Bayer Pharmaceuticals Corporation Derives tetrahydro-5h-pyrimido[4,5-d]azepine convenant pour le traitement de maladies associees au recepteur 5-ht2c
JP2008526734A (ja) * 2004-12-31 2008-07-24 エスケー ケミカルズ カンパニー リミテッド 糖尿及び肥満治療予防に有効なキナゾリン誘導体
US20090209536A1 (en) * 2007-06-17 2009-08-20 Kalypsys, Inc. Aminoquinazoline cannabinoid receptor modulators for treatment of disease
CA2896731A1 (fr) * 2012-12-28 2014-07-03 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Inhibiteurs du complexe usp1/uaf1 desubiquitinase et leurs utilisations
AU2023261809A1 (en) * 2022-04-29 2024-12-05 Asieris Pharmaceuticals (Shanghai) Co., Ltd. Pyrimidine compound, method for preparing same, and pharmaceutical use thereof
TW202444707A (zh) * 2023-04-04 2024-11-16 大陸商江蘇亞虹醫藥科技股份有限公司 泛素特異性蛋白酶１抑制劑、其製備方法及其醫藥用途

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