Ubiquitin-specific processing protease 1 (USP1) inhibitors for the treatment of solid tumors

Abstract

The present disclosure provides USP1 inhibitors for use in the treatment of cancer and methods of using the inhibitors to treat cancer.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 302,891, filed January 25, 2022, U.S. Provisional Application No. 63 / 375,601, filed September 14, 2022, and U.S. Provisional Application No. 63 / 384,554, filed November 21, 2022 (each of which is incorporated herein by reference in its entirety).

[0002] REFERENCE TO ELECTRONICALLY SUBMITTED SEQUENCE LISTING The contents of the electronically submitted sequence listing (Name: 4195_029PC03_Seqlisting_ST26; Size: 3,002 bytes; Date Created: January 20, 2023) are incorporated herein by reference in their entirety.

[0003] FIELD OF THEINVENTION The present disclosure relates to a method of using a ubiquitin-specific processing protease 1 (USP1) inhibitor to treat solid tumors, and to the use of a USP1 inhibitor to treat solid tumors, wherein the USP1 inhibitor is provided in a therapeutically effective amount. Therapeutically effective dosing regimens are provided herein. [Background technology]

[0004] Substituted pyrazolopyrimidines such as 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine are inhibitors of USP1, which has been identified as a target for cancer therapy. 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine inhibitors can inhibit USP1 with low nM potency and are selective for USP1 over other deubiquitinase family members. Furthermore, the USP1 inhibitors are selectively active in a specific subset of cell lines and do not exhibit extensive cytotoxicity. However, there is a significant need to identify specific dosing regimens of USP1 inhibitors that can elicit effective responses in humans while avoiding dose-limiting adverse effects.

[0005] Quick Overview Provided herein is a dosing regimen for administering USP1 inhibitors for the treatment of solid tumors.For example, provided herein is a method for treating solid tumors in human patients, comprising administering to the patient about 75mg to about 2500mg of ubiquitin-specific processing protease 1 (USP1) inhibitor 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (Compound I), or a salt, solvate, hydrate or cocrystal of Compound I in an amount equivalent to about 75mg to about 2500mg of Compound I. Also provided herein is a method of treating a solid tumor in a human patient, the method comprising administering to the patient about 75 mg to about 1000 mg of the ubiquitin-specific processing protease 1 (USP1) inhibitor 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (Compound I), or a salt, solvate, hydrate, or co-crystal of Compound I in an amount equivalent to about 75 mg to about 1000 mg of Compound I. Also provided herein is a method for treating a solid tumor in a human patient, the method comprising administering to the patient about 1000 mg to about 2500 mg of ubiquitin-specific processing protease 1 (USP1) inhibitor Compound I, or a salt, solvate, hydrate, or cocrystal of Compound I in an amount equivalent to about 1000 mg to about 2500 mg of Compound I.

[0006] In some embodiments, the USP1 inhibitor is administered in an amount of about 75 mg, or the salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 75 mg of the USP1 inhibitor.In some embodiments, the USP1 inhibitor is administered in an amount of about 100 mg, or the salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 100 mg of the USP1 inhibitor.In some embodiments, the USP1 inhibitor is administered in an amount of about 150 mg, or the salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 150 mg of the USP1 inhibitor.In some embodiments, the USP1 inhibitor is administered in an amount of about 200 mg, or the salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 200 mg of the USP1 inhibitor. In some embodiments, the USP1 inhibitor is administered in an amount of about 250 mg, or the salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 250 mg of the USP1 inhibitor.In some embodiments, the USP1 inhibitor is administered in an amount of about 300 mg, or the salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 300 mg of the USP1 inhibitor.In some embodiments, the USP1 inhibitor is administered in an amount of about 350 mg, or the salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 350 mg of the USP1 inhibitor.In some embodiments, the USP1 inhibitor is administered in an amount of about 400 mg, or the salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 400 mg of the USP1 inhibitor. In some embodiments, the USP1 inhibitor is administered in an amount of about 450 mg, or the salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 450 mg of the USP1 inhibitor.In some embodiments, the USP1 inhibitor is administered in an amount of about 500 mg, or the salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 500 mg of the USP1 inhibitor.In some embodiments, the USP1 inhibitor is administered in an amount of about 550 mg, or the salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 550 mg of the USP1 inhibitor.In some embodiments, the USP1 inhibitor is administered in an amount of about 600 mg, or the salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 600 mg of the USP1 inhibitor.In some embodiments, the USP1 inhibitor is administered in an amount of about 650 mg, or the salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 650 mg of the USP1 inhibitor.In some embodiments, the USP1 inhibitor is administered in an amount of about 700 mg, or the salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 700 mg of the USP1 inhibitor.In some embodiments, the USP1 inhibitor is administered in an amount of about 750 mg, or the salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 750 mg of the USP1 inhibitor.In some embodiments, the USP1 inhibitor is administered in an amount of about 800 mg, or the salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 800 mg of the USP1 inhibitor. In some embodiments, the USP1 inhibitor is administered in an amount of about 850 mg, or the salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 850 mg of the USP1 inhibitor.In some embodiments, the USP1 inhibitor is administered in an amount of about 900 mg, or the salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 900 mg of the USP1 inhibitor.In some embodiments, the USP1 inhibitor is administered in an amount of about 950 mg, or the salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 950 mg of the USP1 inhibitor.In some embodiments, the USP1 inhibitor is administered in an amount of about 1000 mg, or the salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 1000 mg of the USP1 inhibitor. In some embodiments, the USP1 inhibitor is administered in an amount of about 1050 mg, or the salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 1050 mg of the USP1 inhibitor.In some embodiments, the USP1 inhibitor is administered in an amount of about 1100 mg, or the salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 1100 mg of the USP1 inhibitor.In some embodiments, the USP1 inhibitor is administered in an amount of about 1150 mg, or the salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 1150 mg of the USP1 inhibitor.In some embodiments, the USP1 inhibitor is administered in an amount of about 1120 mg, or the salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 1200 mg of the USP1 inhibitor.In some embodiments, the USP1 inhibitor is administered in an amount of about 1250 mg, or the salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 1250 mg of the USP1 inhibitor.In some embodiments, the USP1 inhibitor is administered in an amount of about 1300 mg, or the salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 1300 mg of the USP1 inhibitor.In some embodiments, the USP1 inhibitor is administered in an amount of about 1350 mg, or the salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 1350 mg of the USP1 inhibitor.In some embodiments, the USP1 inhibitor is administered in an amount of about 1400 mg, or the salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 1400 mg of the USP1 inhibitor. In some embodiments, the USP1 inhibitor is administered in an amount of about 1450 mg, or the salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 1450 mg of the USP1 inhibitor.In some embodiments, the USP1 inhibitor is administered in an amount of about 1500 mg, or the salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 1500 mg of the USP1 inhibitor.In some embodiments, the USP1 inhibitor is administered in an amount of about 1550 mg, or the salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 1550 mg of the USP1 inhibitor.In some embodiments, the USP1 inhibitor is administered in an amount of about 1600 mg, or the salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 1600 mg of the USP1 inhibitor. In some embodiments, the USP1 inhibitor is administered in an amount of about 1650 mg, or the salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 1650 mg of the USP1 inhibitor.In some embodiments, the USP1 inhibitor is administered in an amount of about 1700 mg, or the salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 1700 mg of the USP1 inhibitor.In some embodiments, the USP1 inhibitor is administered in an amount of about 1750 mg, or the salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 1750 mg of the USP1 inhibitor.In some embodiments, the USP1 inhibitor is administered in an amount of about 1800 mg, or the salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 1800 mg of the USP1 inhibitor.In some embodiments, the USP1 inhibitor is administered in an amount of about 1850 mg, or the salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 1850 mg of the USP1 inhibitor.In some embodiments, the USP1 inhibitor is administered in an amount of about 1900 mg, or the salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 1900 mg of the USP1 inhibitor.In some embodiments, the USP1 inhibitor is administered in an amount of about 1950 mg, or the salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 1950 mg of the USP1 inhibitor. In some embodiments, the USP1 inhibitor is administered in an amount of about 2000 mg, or the salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 2000 mg of the USP1 inhibitor.In some embodiments, the USP1 inhibitor is administered in an amount of about 2100 mg, or the salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 2100 mg of the USP1 inhibitor.In some embodiments, the USP1 inhibitor is administered in an amount of about 2200 mg, or the salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 2200 mg of the USP1 inhibitor.In some embodiments, the USP1 inhibitor is administered in an amount of about 2300 mg, or the salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 2300 mg of the USP1 inhibitor. In some embodiments, the USP1 inhibitor is administered in an amount of about 2400 mg, or the salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 2400 mg of the USP1 inhibitor.In some embodiments, the USP1 inhibitor is administered in an amount of about 2500 mg, or the salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 2500 mg of the USP1 inhibitor.

[0007] In some embodiments, the USP1 inhibitor is administered in an amount of about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg , about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, or a range between any of the values ​​recited in this paragraph, or a salt of the USP1 inhibitor, The solvate, hydrate or co-crystal is about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 250 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 350 mg, about 3600 mg, about 3700 mg, about 3800 mg, about 3900 mg, about 4000 mg, about 4000 mg, about 4000 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 700 mg, In one embodiment, the compound is administered in an amount equivalent to about 1000 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, or a range between any of the values ​​recited in this paragraph.

[0008] In some embodiments, the USP1 inhibitor, or its salt, solvate, hydrate or cocrystal, is administered approximately once a day. In some embodiments described in the above paragraph, the USP1 inhibitor is administered as divided doses over the course of a day. For example, in some embodiments, the USP1 inhibitor is administered twice a day (e.g., when the dosage is 1000 mg or an equivalent amount, the USP1 inhibitor is administered in a first dosage of 500 mg and a second dosage of 500 mg on the same day, where the first dosage and the second dosage are not administered simultaneously). The first dosage and the second dosage can be the same amount or different amounts.

[0009] In some embodiments, the USP1 inhibitor, or a salt, solvate, hydrate, or cocrystal thereof, is administered orally.

[0010] In some embodiments, the cancer is ovarian cancer. In some embodiments, the ovarian cancer is serous ovarian cancer.

[0011] In some embodiments, the cancer is breast cancer. In some embodiments, the patient has previously received platinum-based chemotherapy. In some embodiments, the cancer is platinum-sensitive. In some embodiments, the cancer is platinum-resistant. In some embodiments, the breast cancer is human epidermal growth factor receptor 2 (HER2) negative. In some embodiments, the breast cancer is triple-negative breast cancer.

[0012] In some embodiments, the cancer has a mutation in BRCA1. In some embodiments, the cancer has a mutation in BRCA2.

[0013] In some embodiments, the breast cancer is germline breast cancer susceptibility gene mutation (gBRCAm) breast cancer. In some embodiments, the breast cancer is metastatic.

[0014] In some embodiments, the patient has previously been treated with at least one systemic chemotherapy for metastatic disease. In some embodiments, the cancer is selected from the group consisting of DNA damage repair pathway deficient cancer, homologous-recombination deficient cancer, cancer with cancer cells having a mutation in the gene encoding p53, and cancer with cancer cells having a loss-of-function mutation in the gene encoding p53. In some embodiments, the cancer is selected from the group consisting of lung cancer, non-small cell lung cancer (NSCLC), colon cancer, bladder cancer, osteosarcoma, ovarian cancer, skin cancer, and breast cancer.

[0015] In some embodiments, the cancer comprises cancer cells with elevated levels of RAD18 protein and / or RAD18 mRNA. In some embodiments, the cancer comprises cancer cells with elevated levels of RAD51 protein and / or RAD51 mRNA. In some embodiments, the elevated level of RAD51 is elevated levels of RAD51 protein foci. In some embodiments, at least 10% of cells in the S / G2 phase of the cell cycle in a sample obtained from the cancer are RAD51 positive.

[0016] In some embodiments, the cancer is recurrent. In some embodiments, the patient has previously been treated with a PARP inhibitor (PARPi). In some embodiments, the cancer is a PARP inhibitor resistant or refractory cancer.

[0017] In some embodiments, Compound I is administered as a co-crystal with a pharma- ceutically acceptable acid. In some embodiments, the pharma-ceutically acceptable acid is gentisic acid.

[0018] In some embodiments, the USP1 inhibitor, or a salt, solvate, hydrate, or cocrystal thereof, is administered at least 3 times, at least 4 times, or at least 5 times, or at least times, or at least 15 times, or for at least 20 days, or at least 25 days, or at least 30 days, or at least 60 days, or at least 90 days, or at least 120 days, or at least 150 days, or at least 180 days, or at least 210 days, or at least 240 days, or at least 270 days, or at least 300 days, or at least 330 days, or at least 360 days, or at least 365 days, or more. In some embodiments, the USP1 inhibitor, or a salt, solvate, hydrate, or cocrystal thereof, is administered for a period of at least 3 days, or at least 4 days, or at least 5 days, or at least 10 days, or at least 15 days, or at least 20 days, or at least 25 days, or at least 1 month, or at least 2 months, or at least 3 months, or at least 4 months, or at least 5 months, or at least 6 months, or at least 7 months, or at least 8 months, or at least 9 months, or at least 10 months, or at least 11 months, or at least 1 year, or at least 18 months, or at least 2 years, or more.

[0019] Also provided herein is a USP1 inhibitor Compound I, or a salt, solvate, hydrate, or co-crystal thereof, for use in the methods provided herein. [Brief description of the drawings]

[0020] [Figure 1] FIG. 1 is an X-ray powder diffraction pattern ("XRPD") corresponding to crystalline form A (see Example 1).

[0021] [Diagram 2] FIG. 2 is a differential scanning calorimetry thermogram ("DSC") and a thermogravimetric analysis thermogram ("TGA") corresponding to crystalline form A (see Example 1).

[0022] [Diagram 3] FIG. 3 is the asymmetric unit of crystalline form A from the single crystal structure (see Example 1).

[0023] [Figure 4] FIG. 4 is an XRPD pattern corresponding to crystalline form 2 (see Example 2).

[0024] [Diagram 5] FIG. 5 is a DSC and TGA thermogram corresponding to crystalline Form 2 (see Example 2).

[0025] [Figure 6] FIG. 6 is the asymmetric unit of crystalline form 2 from the single crystal structure (see Example 2).

[0026] [Figure 7] FIG. 7 is the plasma concentration versus time profile of crystalline Form A following a 300 mg / kg dose in NOD / SCID mice (see Example 3).

[0027] [Figure 8] FIG. 8 is the plasma concentration versus time profile of crystalline Form 2 following a 300 mg / kg dose in NOD / SCID mice (see Example 3).

[0028] [Figure 9] FIG. 9 is the brain and plasma concentration versus time profile of crystalline Form 2 following repeated oral dosing of 100 and 300 mg / kg QD in NOD / SCID female mice (see Example 4).

[0029] [Figure 10] FIG. 10 is the brain and plasma concentration versus time profile of crystalline Form 2 following oral dosing of 100 mg / kg in SD male and female rats (see Example 5).

[0030] [Figure 11]FIG. 11 provides a dose escalation scheme for administration of the USP1 inhibitor 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (Compound I) (see Example 6).

[0031] Detailed Description of the Invention I. Definition To facilitate understanding of the disclosure set forth herein, a number of terms are defined below.

[0032] Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry and pharmacology described herein are those well known and commonly used in the art. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0033] The XRPD, DSC and TGA characterization data referred to throughout this application and the claims have been determined using the instruments and conditions detailed under the subheading "Instrumental Conditions" at the beginning of the Examples section.

[0034] In this specification and the appended claims, the singular forms "a", "an" and "the" include plural references unless the context clearly dictates otherwise. The term "a" (or "an"), as well as the terms "one or more" and "at least one" can be used interchangeably herein. In certain embodiments, the term "a" or "an" means "single". In other embodiments, the term "a" or "an" includes "two or more" or "plurality".

[0035] Furthermore, "and / or" as used herein is considered as a specific disclosure of two specified features or components, each of which may or may not have the other feature or component. Thus, the term "and / or" as used herein in expressions such as "A and / or B" is intended to include "A and B", "A or B", "A" (single), and "B" (single). Similarly, the term "and / or" as used in expressions such as "A, B and / or C" is intended to include each of the following aspects: A, B and C; A, B or C; A or C; A or B; B or C; A and C; A and B; B and C; A (single); B (single); and C (single).

[0036] As used herein, "USP1" and "ubiquitin-specific processing protease 1" refer to a naturally occurring polypeptide or a USP1-encoding polynucleotide. The term "USP1" encompasses "full-length" unprocessed USP1 polypeptides, as well as forms of USP1 that result from processing in cells (e.g., removal of the signal peptide). The term also encompasses those encoded by naturally occurring variants of USP1, such as splice variants and allelic variants. The USP1 polypeptides described herein can be isolated from a variety of sources, such as from human tissue types or another source, or can be prepared by recombinant or synthetic methods. Human USP1 sequences are known and include, for example, the sequence (including isoforms) publicly available as UniProt No. 094782. As used herein, the term "human USP1 protein" refers to the USP1 protein as set forth in SEQ ID NO: 1: (SEQ ID NO:1) This refers to the USP1 protein comprising the amino acid sequence

[0037] USP1 is a deubiquitinase that acts as part of a complex with UAF1. The "deubiquitinase activity" of USP1 includes its ability to deubiquitinate as part of the USP1-UAF1 complex.

[0038] The term "reduction" or "reduce" or "inhibition" or "inhibiting" refers to the decrease or cessation of a phenotypic characteristic, or the decrease or cessation of the incidence, extent or likelihood of said characteristic. "Reduce" or "inhibit" refers to the decrease, decrease or cessation of an activity, function and / or amount compared to a standard. In some embodiments, "reduce" or "inhibit" refers to the ability to cause an overall reduction of 20% or more. In some embodiments, "reduce" or "inhibit" refers to the ability to cause an overall reduction of 50% or more. In some embodiments, "reduce" or "inhibit" refers to the ability to cause an overall reduction of 75%, 85%, 90%, 95% or more. In some embodiments, the amount is inhibited or reduced over a period of time compared to a control over the same period of time.

[0039] The term "USP1 inhibitor" or "inhibitor of USP1" refers to a compound that can inhibit one or more activities or functions of the USP1 protein. It should be understood that one or more activities or functions of the USP1 protein can be inhibited in vitro or in vivo. Non-limiting examples of USP1 activities and functions include deubiquitinase activity and the formation of a complex with UAF1. See, for example, International Publication No. WO 2020 / 132269 (incorporated herein by reference in its entirety).

[0040] The term "6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine" or "Compound I" refers to the compound having the following structure: [ka] It refers to a compound having the formula:

[0041] The term "subject" refers to an animal, including, but not limited to, a primate (e.g., a human), cow, sheep, goat, horse, dog, cat, rabbit, rat or mouse. The terms "subject" and "patient" are used interchangeably herein in reference to a mammalian subject, such as a human subject.

[0042] The terms "treat", "treating" and "treatment" are meant to include an approach to obtain beneficial or desired clinical results. As used herein, "treatment" encompasses the administration or application of a therapeutic agent to a disease in a mammal, including a human. For purposes of this disclosure, beneficial or desired clinical results include, but are not limited to, any one or more of the following: alleviation of one or more symptoms, reduction in the extent of the disease, prevention or delay of the spread (e.g., metastasis) of the disease, prevention or delay of recurrence of the disease, delay or slowing of the progression of the disease, amelioration of the disease state, inhibition of the disease or disease progression, inhibition or slowing of the disease or its progression, prevention of its onset, and remission (whether partial or total). "Treatment" also encompasses reduction of the pathological consequences of a proliferative disease. The methods provided herein contemplate any one or more of these aspects of treatment. As above, the term treatment does not require 100% elimination of all aspects of the disorder.

[0043] In relation to cancer, the terms "treat," "treating," and "treatment" include, but are not limited to, inhibiting the proliferation of cancer cells, inhibiting the replication of cancer cells, reducing the overall tumor burden, and delaying, halting, or slowing tumor growth, tumor progression, or tumor metastasis.

[0044] As used herein, the terms "cancer" and "tumor" refer to or describe a physiological condition in a mammal in which a cell population is characterized by unregulated cell proliferation. These terms include solid cancers. Examples of cancer include, but are not limited to, DNA repair pathway deficient cancers and homologous recombination deficiency (HRD) cancers. Further examples of cancer include, but are not limited to, ovarian cancer, breast cancer (including triple-negative breast cancer), lung cancer (including non-small cell lung cancer (NSCLC)), and osteosarcoma. The cancer may be wild-type BRCA1 and / or BRCA2. The cancer may also be BRCA1 (somatic and / or germline) mutant and / or BRCA2 (somatic and / or germline) mutant. The cancer may further be PARP inhibitor-resistant or resistant cancer, or PARP inhibitor-resistant or resistant BRCA1 or BRCA2 mutant cancer.

[0045] A "therapeutically effective amount" of a substance is also an amount in which the toxic or detrimental effects of the substance are outweighed by the therapeutically beneficial effects. A therapeutically effective amount can be delivered in one or more administrations. A therapeutically effective amount refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic effect.

[0046] The terms "administer," "administering," "administration," and the like refer to methods that can be used to enable delivery of a therapeutic agent to a desired site of biological action. Administration techniques that can be employed in the agents and methods described herein are described, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa.

[0047] The terms "pharmaceutical formulation" and "pharmaceutical composition" refer to a formulation that is in a form such that the biological activity of the active ingredient is effective and that does not contain additional ingredients that are unacceptably toxic to the subject to which it is administered. Such formulations may be sterile.

[0048] The terms "pharmaceutically acceptable carrier", "pharmaceutically acceptable excipient", "physiologically acceptable carrier" or "physiologically acceptable excipient" refer to a pharmaceutically acceptable substance, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. A pharmaceutically acceptable carrier is non-toxic to a recipient at the dosage and concentration employed and is compatible with the other components of the formulation. A pharmaceutically acceptable carrier is one that is suitable for the formulation in which it is used. In some embodiments, each component is "pharmaceutically acceptable" in the sense of being compatible with the other components of the pharmaceutical formulation, suitable for use in contact with human and animal tissues or organs without excessive toxicity, irritation, allergic response, immunogenicity or other problems or complications, and commensurate with a reasonable benefit / risk ratio. See Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 5th Edition, Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; and Handbook of Pharmaceutical Additives, 3rd Edition, Ash and Ash Eds., Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, Gibson Ed., CRC Press LLC: Boca Raton, FL, 2004, all of which are incorporated herein by reference.

[0049] The terms "active ingredient" and "active substance" refer to a compound administered to a subject, alone or in combination with one or more pharma- ceutically acceptable excipients, for the treatment, prevention, or amelioration of one or more symptoms of a condition, disorder, or disease. As used herein, "active ingredient" and "active substance" may be an optically active isomer of a compound described herein.

[0050] The terms "drug," "therapeutic agent," and "chemotherapeutic agent" refer to a chemical compound or pharmaceutical composition thereof that is administered to a subject for the treatment, prevention, or amelioration of one or more symptoms of a condition, disorder, or disease.

[0051] The term "solvate" refers to a compound provided herein or its salt, which further comprises a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces.When the solvent is water, the solvate is a hydrate.When the solvent comprises ethanol, the compound can be an ethanol solvate.

[0052] The term "polymorph" as used herein refers to a crystalline form of a compound or its salt, hydrate or solvate in a particular crystal packing arrangement. All polymorphs have the same elemental composition. The term "crystalline" as used herein refers to a solid state form consisting of an ordered arrangement of structural units. Different crystalline forms of the same compound or its salt, cocrystal, hydrate or solvate arise from different packing of molecules in the solid state, resulting in different crystal symmetries and / or unit cell parameters. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. See, e.g., Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton PA, 173 (1990); The United States Pharmacopeia, 23rd ed., 1843-1844 (1995), incorporated herein by reference.

[0053] Crystal forms are most commonly characterized by X-ray powder diffraction (XRPD). The XRPD pattern of reflected light (peaks, typically expressed in °2θ) is generally considered the fingerprint of a particular crystal form. The relative intensities of XRPD peaks can vary widely, especially depending on the sample preparation technique, crystal size distribution, filters, sample mounting procedures, and the particular instrument used. In some embodiments, new peaks may be observed or existing peaks may disappear, depending on the type or settings of the instrument. In some embodiments, a particular peak in an XRPD pattern may appear as a singlet, doublet, triplet, quartet, or multiplet, depending on the type or settings of the instrument, the sensitivity of the instrument, the measurement conditions, and / or the purity of the crystal form. In some embodiments, a particular XRPD peak may appear as a symmetric or asymmetric shape, e.g., with a shoulder. Those skilled in the art who understand these variations can use XRPD, and other known physicochemical techniques, to identify or confirm the characteristics or properties of a particular crystal form.

[0054] The term "amorphous" as applied to chemical compounds refers to a state in which the material lacks long-range order at the molecular level and may exhibit the physical properties of a solid or liquid, depending on the temperature. Typically, such materials do not exhibit a characteristic X-ray diffraction pattern and, while exhibiting the properties of a solid, are more formally described as liquids. Upon heating, a change from solid to liquid occurs, which is typically characterized by a second-order change of state (the "glass transition").

[0055] The term "anhydrous" as applied to a compound refers to the solid state in which the compound does not contain structural water within the crystal lattice.

[0056] The term "about" as used herein includes the stated numerical value ±10%. Thus, "about 10" means 9 to 11. As will be understood by those skilled in the art, reference to "about" a value or parameter herein includes (and describes) aspects directed to the value or parameter itself. For example, a description that refers to "about X" also includes a description of "X".

[0057] Unless the context otherwise requires, the terms "comprise," "comprises," and "comprising" are used with the rationale and clear understanding that they are to be interpreted inclusively rather than exclusively, and that applicant intends to so interpret each of these terms in interpreting this patent, including the claims that follow.

[0058] II. Methods of Treating Cancer with USP1 Inhibitors Provided herein are methods of treating cancer, e.g., solid tumors, with a USP1 inhibitor (e.g., Compound I, or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal thereof).

[0059] In some embodiments, the method includes administering about 75 mg to about 1000 mg of a USP1 inhibitor (e.g., Compound I) or administering a salt, solvate, hydrate, or cocrystal thereof in an amount equivalent to about 75 mg to about 100 mg of the USP1 inhibitor. In some embodiments, the method includes administering about 75 mg of a USP1 inhibitor (e.g., Compound I) or administering a salt, solvate, hydrate, or cocrystal thereof in an amount equivalent to about 75 mg of the USP1 inhibitor. In some embodiments, the method includes administering about 100 mg of a USP1 inhibitor (e.g., Compound I) or administering a salt, solvate, hydrate, or cocrystal thereof in an amount equivalent to about 100 mg of the USP1 inhibitor. In some embodiments, the method includes administering about 150 mg of a USP1 inhibitor (e.g., Compound I) or administering a salt, solvate, hydrate, or cocrystal thereof in an amount equivalent to about 150 mg of the USP1 inhibitor. In some embodiments, the method includes administering about 200 mg of a USP1 inhibitor (e.g., compound I) or administering a salt, solvate, hydrate or cocrystal thereof in an amount equivalent to about 200 mg of the USP1 inhibitor. In some embodiments, the method includes administering about 250 mg of a USP1 inhibitor (e.g., compound I) or administering a salt, solvate, hydrate or cocrystal thereof in an amount equivalent to about 250 mg of the USP1 inhibitor. In some embodiments, the method includes administering about 300 mg of a USP1 inhibitor (e.g., compound I) or administering a salt, solvate, hydrate or cocrystal thereof in an amount equivalent to about 300 mg of the USP1 inhibitor. In some embodiments, the method includes administering about 350 mg of a USP1 inhibitor (e.g., compound I) or administering a salt, solvate, hydrate or cocrystal thereof in an amount equivalent to about 350 mg of the USP1 inhibitor. In some embodiments, the method includes administering about 400 mg of a USP1 inhibitor (e.g., Compound I) or administering a salt, solvate, hydrate or cocrystal thereof in an amount equivalent to about 450 mg of the USP1 inhibitor. In some embodiments, the method includes administering about 450 mg of a USP1 inhibitor (e.g., Compound I) or administering a salt, solvate, hydrate or cocrystal thereof in an amount equivalent to about 400 mg of the USP1 inhibitor.In some embodiments, the method includes administering about 500 mg of a USP1 inhibitor (e.g., compound I) or administering a salt, solvate, hydrate or cocrystal thereof in an amount equivalent to about 500 mg of the USP1 inhibitor. In some embodiments, the method includes administering about 550 mg of a USP1 inhibitor (e.g., compound I) or administering a salt, solvate, hydrate or cocrystal thereof in an amount equivalent to about 550 mg of the USP1 inhibitor. In some embodiments, the method includes administering about 600 mg of a USP1 inhibitor (e.g., compound I) or administering a salt, solvate, hydrate or cocrystal thereof in an amount equivalent to about 600 mg of the USP1 inhibitor. In some embodiments, the method includes administering about 650 mg of a USP1 inhibitor (e.g., compound I) or administering a salt, solvate, hydrate or cocrystal thereof in an amount equivalent to about 650 mg of the USP1 inhibitor. In some embodiments, the method includes administering about 700 mg of a USP1 inhibitor (e.g., compound I) or administering a salt, solvate, hydrate or cocrystal thereof in an amount equivalent to about 700 mg of the USP1 inhibitor. In some embodiments, the method includes administering about 750 mg of a USP1 inhibitor (e.g., compound I) or administering a salt, solvate, hydrate or cocrystal thereof in an amount equivalent to about 750 mg of the USP1 inhibitor. In some embodiments, the method includes administering about 800 mg of a USP1 inhibitor (e.g., compound I) or administering a salt, solvate, hydrate or cocrystal thereof in an amount equivalent to about 800 mg of the USP1 inhibitor. In some embodiments, the method includes administering about 850 mg of a USP1 inhibitor (e.g., compound I) or administering a salt, solvate, hydrate or cocrystal thereof in an amount equivalent to about 850 mg of the USP1 inhibitor. In some embodiments, the method includes administering about 900 mg of a USP1 inhibitor (e.g., Compound I) or administering a salt, solvate, hydrate or cocrystal thereof in an amount equivalent to about 900 mg of the USP1 inhibitor. In some embodiments, the method includes administering about 950 mg of a USP1 inhibitor (e.g., Compound I) or administering a salt, solvate, hydrate or cocrystal thereof in an amount equivalent to about 950 mg of the USP1 inhibitor.In some embodiments, the method includes administering about 1000 mg of a USP1 inhibitor (e.g., Compound I), or administering a salt, solvate, hydrate or cocrystal thereof in an amount equivalent to about 1000 mg of the USP1 inhibitor. In some embodiments, the method includes administering about 1050 mg, or about 1100 mg, or about 1150 mg, or about 1200 mg, or about 1250 mg, or about 1300 mg, or about 1350 mg, or about 1400 mg, or about 1450 mg, or about 1500 mg, or about 1550 mg, or about 1600 mg, or about 1650 mg, or about 1700 mg, or about 1750 mg, or about 1800 mg, or about 1850 mg, or about 1900 mg, or about 1950 mg, or about 2000 mg, or about 2100 mg, or about 2200 mg, or about 2300 mg, or about 2400 mg, or about 2500 mg of a USP1 inhibitor (e.g., Compound I); The method includes administering a salt, solvate, hydrate, or cocrystal thereof in an amount equivalent to about 1050 mg, or about 1100 mg, or about 1150 mg, or about 1200 mg, or about 1250 mg, or about 1300 mg, or about 1350 mg, or about 1400 mg, or about 1450 mg, or about 1500 mg, or about 1550 mg, or about 1600 mg, or about 1650 mg, or about 1700 mg, or about 1750 mg, or about 1800 mg, or about 1850 mg, or about 1900 mg, or about 1950 mg, or about 2000 mg, or about 2100 mg, or about 2200 mg, or about 2300 mg, or about 2400 mg, or about 2500 mg of the USP1 inhibitor.

[0060] In some embodiments, the methods include administering about 50 mg to about 2500 mg, or about 50 mg to about 2000 mg, or about 50 mg to about 1500 mg, or about 100 mg to about 1000 mg, or about 200 mg to about 800 mg of a USP1 inhibitor (e.g., Compound I), or administering a salt, solvate, hydrate, or cocrystal thereof in an amount equivalent to about 50 mg to about 2500 mg, or about 50 mg to about 2000 mg, or about 50 mg to about 1500 mg, or about 100 mg to about 1000 mg, or about 200 mg to about 800 mg of the USP1 inhibitor.

[0061] In some embodiments, the method includes administering about 75 mg to about 1000 mg of a USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal). In some embodiments, the method includes administering about 75 mg of a USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal). In some embodiments, the method includes administering about 100 mg of a USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal). In some embodiments, the method includes administering about 150 mg of a USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal). In some embodiments, the method includes administering about 200 mg of a USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal). In some embodiments, the method includes administering about 250 mg of a USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal). In some embodiments, the method includes administering about 300 mg of a USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal). In some embodiments, the method includes administering about 350 mg of a USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal). In some embodiments, the method includes administering about 400 mg of a USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal). In some embodiments, the method includes administering about 500 mg of a USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal). In some embodiments, the method includes administering about 550 mg of a USP1 inhibitor (e.g., Compound I or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal thereof). In some embodiments, the method includes administering about 600 mg of a USP1 inhibitor (e.g., Compound I or a pharma-ceutically acceptable salt, solvate, hydrate, or cocrystal thereof).In some embodiments, the method includes administering about 650 mg of a USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal). In some embodiments, the method includes administering about 700 mg of a USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal). In some embodiments, the method includes administering about 750 mg of a USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal). In some embodiments, the method includes administering about 800 mg of a USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal). In some embodiments, the method includes administering about 850 mg of a USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal). In some embodiments, the method comprises administering about 900 mg of a USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal thereof). In some embodiments, the method comprises administering about 950 mg of a USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal thereof). In some embodiments, the method comprises administering about 1000 mg of a USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal thereof). In some embodiments, the method includes administering about 1050 mg, or about 1100 mg, or about 1150 mg, or about 1200 mg, or about 1250 mg, or about 1300 mg, or about 1350 mg, or about 1400 mg, or about 1450 mg, or about 1500 mg, or about 1550 mg, or about 1600 mg, or about 1650 mg, or about 1700 mg, or about 1750 mg, or about 1800 mg, or about 1850 mg, or about 1900 mg, or about 1950 mg, or about 2000 mg, or about 2100 mg, or about 2200 mg, or about 2300 mg, or about 2400 mg, or about 2500 mg of a USP1 inhibitor (e.g., Compound I or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal thereof).

[0062] In some embodiments, the methods include administering about 50 mg to about 2500 mg, or about 50 mg to about 2000 mg, or about 50 mg to about 1500 mg, or about 100 mg to about 1000 mg, or about 200 mg to about 800 mg of a USP1 inhibitor (e.g., Compound I or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal thereof).

[0063] In some embodiments, the administration is oral administration. The method may include administering the USP1 inhibitor about once a day. In some embodiments described in the above paragraph, the USP1 inhibitor is administered as divided doses over a day. For example, in some embodiments, the USP1 inhibitor is administered twice a day (e.g., when the dosage is 1000 mg or an equivalent amount, the USP1 inhibitor is administered in a first dosage of 500 mg and a second dosage of 500 mg on the same day, where the first dosage and the second dosage are not administered simultaneously). The first dosage and the second dosage may be the same amount or different amounts.

[0064] The method may include administering the USP1 inhibitor at least twice (e.g., for 2 consecutive days). The method may include administering the USP1 inhibitor at least three times (e.g., for 3 consecutive days). The method may include administering the USP1 inhibitor at least four times (e.g., for 4 consecutive days). The method may include administering the USP1 inhibitor at least five times (e.g., for 5 consecutive days). The method may include administering the USP1 inhibitor about 10 times (e.g., for about 10 consecutive days). The method may include administering the USP1 inhibitor about 15 times (e.g., for about 15 consecutive days). The method may include administering the USP1 inhibitor about 20 times (e.g., for about 20 consecutive days). The method may include administering the USP1 inhibitor about 25 times (e.g., for about 25 consecutive days). The method may include administering the USP1 inhibitor about 28 times (e.g., for about 28 consecutive days).

[0065] The method may include administering the USP1 inhibitor for a period of at least 1 month, or at least 2 months, or at least 3 months, or at least 4 months, or at least 5 months, or at least 6 months, or at least 7 months, or at least 8 months, or at least 9 months, or at least 10 months, or at least 11 months, or at least 1 year, or at least 18 months, or at least 2 years, or more.

[0066] The method may include administering the USP1 inhibitor once every 21 days (approximately once every 3 weeks). The method may include administering the USP1 inhibitor at least twice (e.g., about 21 days apart). The method may include administering the USP1 inhibitor at least three times (e.g., about 21 days apart). The method may include administering the USP1 inhibitor at least four times (e.g., about 21 days apart). The method may include administering the USP1 inhibitor at least five times (e.g., about 21 days apart).

[0067] Also provided herein is the use of USP1 inhibitor (e.g., compound I or its pharma- ceutically acceptable salt, solvate, hydrate or cocrystal) in medicine for treating solid tumors.In some embodiments, the medicine is formulated for oral administration.

[0068] In some embodiments, such a medicament contains about 75 mg to about 1000 mg of a USP1 inhibitor (e.g., Compound I), or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal thereof, in an amount equivalent to about 75 mg to about 1000 mg of the USP1 inhibitor. In some embodiments, such a medicament contains about 75 mg of a USP1 inhibitor (e.g., Compound I), or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal thereof, in an amount equivalent to about 75 mg of the USP1 inhibitor. In some embodiments, such a medicament contains about 100 mg of a USP1 inhibitor (e.g., Compound I), or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal thereof, in an amount equivalent to about 100 mg of the USP1 inhibitor. In some embodiments, such a medicament contains about 150 mg of a USP1 inhibitor (e.g., Compound I), or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal thereof, in an amount equivalent to about 150 mg of the USP1 inhibitor. In some embodiments, such a medicament comprises about 200 mg of a USP1 inhibitor (e.g., compound I) or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal thereof in an amount equivalent to about 200 mg of the USP1 inhibitor. In some embodiments, such a medicament comprises about 250 mg of a USP1 inhibitor (e.g., compound I) or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal thereof in an amount equivalent to about 250 mg of the USP1 inhibitor. In some embodiments, such a medicament comprises about 300 mg of a USP1 inhibitor (e.g., compound I) or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal thereof in an amount equivalent to about 300 mg of the USP1 inhibitor. In some embodiments, such a medicament comprises about 350 mg of a USP1 inhibitor (e.g., compound I) or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal thereof in an amount equivalent to about 350 mg of the USP1 inhibitor. In some embodiments, such a medicament comprises about 400 mg of a USP1 inhibitor (e.g., Compound I), or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal thereof equivalent to about 400 mg of the USP1 inhibitor.In some embodiments, such a medicament comprises about 450 mg of a USP1 inhibitor (e.g., compound I) or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal thereof in an amount equivalent to about 450 mg of the USP1 inhibitor. In some embodiments, such a medicament comprises about 500 mg of a USP1 inhibitor (e.g., compound I) or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal thereof in an amount equivalent to about 500 mg of the USP1 inhibitor. In some embodiments, such a medicament comprises about 550 mg of a USP1 inhibitor (e.g., compound I) or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal thereof in an amount equivalent to about 550 mg of the USP1 inhibitor. In some embodiments, such a medicament comprises about 600 mg of a USP1 inhibitor (e.g., compound I) or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal thereof in an amount equivalent to about 600 mg of the USP1 inhibitor. In some embodiments, such a medicament comprises about 650 mg of a USP1 inhibitor (e.g., compound I) or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal thereof in an amount equivalent to about 650 mg of the USP1 inhibitor. In some embodiments, such a medicament comprises about 700 mg of a USP1 inhibitor (e.g., compound I) or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal thereof in an amount equivalent to about 700 mg of the USP1 inhibitor. In some embodiments, such a medicament comprises about 750 mg of a USP1 inhibitor (e.g., compound I) or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal thereof in an amount equivalent to about 750 mg of the USP1 inhibitor. In some embodiments, such a medicament comprises about 800 mg of a USP1 inhibitor (e.g., compound I) or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal thereof in an amount equivalent to about 800 mg of the USP1 inhibitor. In some embodiments, such a medicament comprises about 850 mg of a USP1 inhibitor (e.g., Compound I), or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal thereof, equivalent to about 850 mg of the USP1 inhibitor. In some embodiments, such a medicament comprises about 900 mg of a USP1 inhibitor (e.g., Compound I), or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal thereof, equivalent to about 900 mg of the USP1 inhibitor.In some embodiments, such a medicament comprises about 950 mg of a USP1 inhibitor (e.g., Compound I), or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal thereof, equivalent to about 950 mg of the USP1 inhibitor. In some embodiments, such a medicament comprises about 1000 mg of a USP1 inhibitor (e.g., Compound I), or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal thereof, equivalent to about 1000 mg of the USP1 inhibitor. In some embodiments, such medicaments contain about 1050 mg, or about 1100 mg, or about 1150 mg, or about 1200 mg, or about 1250 mg, or about 1300 mg, or about 1350 mg, or about 1400 mg, or about 1450 mg, or about 1500 mg, or about 1550 mg, or about 1600 mg, or about 1650 mg, or about 1700 mg, or about 1750 mg, or about 1800 mg, or about 1850 mg, or about 1900 mg, or about 1950 mg, or about 2000 mg, or about 2100 mg, or about 2200 mg, or about 2300 mg, or about 2400 mg, or about 2500 mg, or about The pharma- ceutically acceptable salt, solvate, hydrate, or co-crystal is contained in an amount equivalent to about 1050 mg, or about 1100 mg, or about 1150 mg, or about 1200 mg, or about 1250 mg, or about 1300 mg, or about 1350 mg, or about 1400 mg, or about 1450 mg, or about 1500 mg, or about 1550 mg, or about 1600 mg, or about 1650 mg, or about 1700 mg, or about 1750 mg, or about 1800 mg, or about 1850 mg, or about 1900 mg, or about 1950 mg, or about 2000 mg, or about 2100 mg, or about 2200 mg, or about 2300 mg, or about 2400 mg, or about 2500 mg of the USP1 inhibitor.In some embodiments, such a medicament comprises a USP1 inhibitor (e.g., Compound I) in an amount equivalent to about 50 mg to about 2500 mg, or about 50 mg to about 2000 mg, or about 50 mg to about 1500 mg, or about 100 mg to about 1000 mg, or about 200 mg to about 800 mg, or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal thereof, in an amount equivalent to about 50 mg to about 2500 mg, or about 50 mg to about 2000 mg, or about 50 mg to about 1500 mg, or about 100 mg to about 1000 mg, or about 200 mg to about 800 mg.

[0069] In some embodiments, such a medicament contains about 75 mg to about 1000 mg of a USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal). In some embodiments, such a medicament contains about 75 mg of a USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal). In some embodiments, such a medicament contains about 100 mg of a USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal). In some embodiments, such a medicament contains about 150 mg of a USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal). In some embodiments, such a medicament contains about 200 mg of a USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal). In some embodiments, such a medicament comprises about 250 mg of a USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal). In some embodiments, such a medicament comprises about 300 mg of a USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal). In some embodiments, such a medicament comprises about 350 mg of a USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal). In some embodiments, such a medicament comprises about 400 mg of a USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal). In some embodiments, such a medicament comprises about 450 mg of a USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal). In some embodiments, such a medicament comprises about 500 mg of a USP1 inhibitor (e.g., Compound I or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal thereof). In some embodiments, such a medicament comprises about 550 mg of a USP1 inhibitor (e.g., Compound I or a pharma-ceutically acceptable salt, solvate, hydrate, or cocrystal thereof).In some embodiments, such a medicament comprises about 600 mg of a USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal). In some embodiments, such a medicament comprises about 650 mg of a USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal). In some embodiments, such a medicament comprises about 700 mg of a USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal). In some embodiments, such a medicament comprises about 750 mg of a USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal). In some embodiments, such a medicament comprises about 800 mg of a USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal). In some embodiments, such a medicament comprises about 850 mg of a USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal). In some embodiments, such a medicament comprises about 900 mg of a USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal). In some embodiments, such a medicament comprises about 950 mg of a USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal). In some embodiments, such a medicament comprises about 1000 mg of a USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal).In some embodiments, such a medicament comprises about 1050 mg, or about 1100 mg, or about 1150 mg, or about 1200 mg, or about 1250 mg, or about 1300 mg, or about 1350 mg, or about 1400 mg, or about 1450 mg, or about 1500 mg, or about 1550 mg, or about 1600 mg, or about 1650 mg, or about 1700 mg, or about 1750 mg, or about 1800 mg, or about 1850 mg, or about 1900 mg, or about 1950 mg, or about 2000 mg, or about 2100 mg, or about 2200 mg, or about 2300 mg, or about 2400 mg, or about 2500 mg of a USP1 inhibitor (e.g., Compound I or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal thereof). In some embodiments, such medicaments contain about 50 mg to about 2500 mg, or about 50 mg to about 2000 mg, or about 50 mg to about 1500 mg, or about 100 mg to about 1000 mg, or about 200 mg to about 800 mg of a USP1 inhibitor (e.g., Compound I or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal thereof).

[0070] In some embodiments, such medicaments are for administration about once a day. In some embodiments, such medicaments are for administration at least twice (e.g., on two consecutive days). In some embodiments, such medicaments are for administration at least three times (e.g., on three consecutive days). In some embodiments, such medicaments are for administration at least four times (e.g., on four consecutive days). In some embodiments, such medicaments are for administration at least five times (e.g., on five consecutive days). In some embodiments, such medicaments are for administration at least five times (e.g., on five consecutive days). In some embodiments, such medicaments are for administration about 28 times (e.g., on about 28 consecutive days). In some embodiments, such medicaments are for administration at least 3 times, at least 4 times, or at least 5 times, or at least times, or at least 15 times, or for at least 20 days, or at least 25 days, or at least 30 days, or at least 60 days, or at least 90 days, or at least 120 days, or at least 150 days, or at least 180 days, or at least 210 days, or at least 240 days, or at least 270 days, or at least 300 days, or at least 330 days, or at least 360 days, or at least 365 days, or longer. In some embodiments, such medicaments are for administration for a period of at least 3 days, or at least 4 days, or at least 5 days, or at least 10 days, or at least 15 days, or at least 20 days, or at least 25 days, or at least 1 month, or at least 2 months, or at least 3 months, or at least 4 months, or at least 5 months, or at least 6 months, or at least 7 months, or at least 8 months, or at least 9 months, or at least 10 months, or at least 11 months, or at least 1 year, or at least 18 months, or at least 2 years, or more.

[0071] In some embodiments, such medicaments are for administration about once every 21 days (about once every 3 weeks). In some embodiments, such medicaments are for administration at least twice (e.g., about 21 days apart). In some embodiments, such medicaments are for administration at least three times (e.g., about 21 days apart). In some embodiments, such medicaments are for administration at least four times (e.g., about 21 days apart). In some embodiments, such medicaments are for administration at least five times (e.g., about 21 days apart).

[0072] In some embodiments, such a medicament is formulated for administration of about 75 mg to about 1000 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal). In some embodiments, such a medicament is formulated for administration of about 75 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal). In some embodiments, such a medicament is formulated for administration of about 100 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal). In some embodiments, such a medicament is formulated for administration of about 150 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal). In some embodiments, such a medicament is formulated for administration of about 200 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal). In some embodiments, such a medicament is formulated for administration of about 250 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal). In some embodiments, such a medicament is formulated for administration of about 300 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal). In some embodiments, such a medicament is formulated for administration of about 350 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal). In some embodiments, such a medicament is formulated for administration of about 400 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal). In some embodiments, such a medicament is formulated for administration of about 450 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal). In some embodiments, such a medicament is formulated for administration of about 500 mg of the USP1 inhibitor (e.g., Compound I or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal thereof).In some embodiments, such a medicament is formulated for administration of about 550 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal). In some embodiments, such a medicament is formulated for administration of about 600 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal). In some embodiments, such a medicament is formulated for administration of about 650 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal). In some embodiments, such a medicament is formulated for administration of about 700 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal). In some embodiments, such a medicament is formulated for administration of about 750 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal). In some embodiments, such a medicament is formulated for administration of about 800 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal). In some embodiments, such a medicament is formulated for administration of about 850 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal). In some embodiments, such a medicament is formulated for administration of about 900 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal). In some embodiments, such a medicament is formulated for administration of about 950 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal). In some embodiments, such a medicament is formulated for administration of about 1000 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal).In some embodiments, such medicaments are formulated for administration of about 1050 mg, or about 1100 mg, or about 1150 mg, or about 1200 mg, or about 1250 mg, or about 1300 mg, or about 1350 mg, or about 1400 mg, or about 1450 mg, or about 1500 mg, or about 1550 mg, or about 1600 mg, or about 1650 mg, or about 1700 mg, or about 1750 mg, or about 1800 mg, or about 1850 mg, or about 1900 mg, or about 1950 mg, or about 2000 mg, or about 2100 mg, or about 2200 mg, or about 2300 mg, or about 2400 mg, or about 2500 mg. In some embodiments, such medicaments are formulated for administration of about 50 mg to about 2500 mg, or about 50 mg to about 2000 mg, or about 50 mg to about 1500 mg, or about 100 mg to about 1000 mg, or about 200 mg to about 800 mg of the USP1 inhibitor (e.g., Compound I or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal thereof).

[0073] In some embodiments, the medicament is formulated to administer about 75 mg of the USP1 inhibitor or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor in an amount equivalent to about 75 mg of the USP1 inhibitor. In some embodiments, the medicament is formulated to administer about 100 mg of the USP1 inhibitor or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor in an amount equivalent to about 100 mg of the USP1 inhibitor. In some embodiments, the medicament is formulated to administer about 150 mg of the USP1 inhibitor or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor in an amount equivalent to about 150 mg of the USP1 inhibitor. In some embodiments, the medicament is formulated to administer about 200 mg of the USP1 inhibitor or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor in an amount equivalent to about 200 mg of the USP1 inhibitor. In some embodiments, the medicament is formulated to administer about 250 mg of the USP1 inhibitor or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor in an amount equivalent to about 250 mg of the USP1 inhibitor. In some embodiments, the medicament is formulated to administer about 300 mg of the USP1 inhibitor or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor in an amount equivalent to about 300 mg of the USP1 inhibitor. In some embodiments, the medicament is formulated to administer about 350 mg of the USP1 inhibitor or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor in an amount equivalent to about 350 mg of the USP1 inhibitor. In some embodiments, the medicament is formulated to administer about 400 mg of the USP1 inhibitor or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor in an amount equivalent to about 400 mg of the USP1 inhibitor. In some embodiments, the medicament is formulated to administer about 450 mg of the USP1 inhibitor or an amount of a salt, solvate, hydrate or cocrystal of the USP1 inhibitor equivalent to about 450 mg of the USP1 inhibitor. In some embodiments, the medicament is formulated to administer about 500 mg of the USP1 inhibitor or an amount of a salt, solvate, hydrate or cocrystal of the USP1 inhibitor equivalent to about 500 mg of the USP1 inhibitor.In some embodiments, the medicament is formulated to administer about 550 mg of the USP1 inhibitor or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor in an amount equivalent to about 550 mg of the USP1 inhibitor. In some embodiments, the medicament is formulated to administer about 600 mg of the USP1 inhibitor or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor in an amount equivalent to about 600 mg of the USP1 inhibitor. In some embodiments, the medicament is formulated to administer about 650 mg of the USP1 inhibitor or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor in an amount equivalent to about 650 mg of the USP1 inhibitor. In some embodiments, the medicament is formulated to administer about 700 mg of the USP1 inhibitor or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor in an amount equivalent to about 700 mg of the USP1 inhibitor. In some embodiments, the medicament is formulated to administer about 750 mg of the USP1 inhibitor or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor in an amount equivalent to about 750 mg of the USP1 inhibitor. In some embodiments, the medicament is formulated to administer about 800 mg of the USP1 inhibitor or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor in an amount equivalent to about 800 mg of the USP1 inhibitor. In some embodiments, the medicament is formulated to administer about 850 mg of the USP1 inhibitor or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor in an amount equivalent to about 850 mg of the USP1 inhibitor. In some embodiments, the medicament is formulated to administer about 900 mg of the USP1 inhibitor or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor in an amount equivalent to about 900 mg of the USP1 inhibitor. In some embodiments, the medicament is formulated to administer about 950 mg of the USP1 inhibitor or an amount of a salt, solvate, hydrate or cocrystal of the USP1 inhibitor equivalent to about 950 mg of the USP1 inhibitor. In some embodiments, the medicament is formulated to administer about 1000 mg of the USP1 inhibitor or an amount of a salt, solvate, hydrate or cocrystal of the USP1 inhibitor equivalent to about 1000 mg of the USP1 inhibitor.In some embodiments, the medicament is formulated to administer about 1050 mg of the USP1 inhibitor or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor in an amount equivalent to about 1050 mg of the USP1 inhibitor. In some embodiments, the medicament is formulated to administer about 1100 mg of the USP1 inhibitor or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor in an amount equivalent to about 1100 mg of the USP1 inhibitor. In some embodiments, the medicament is formulated to administer about 1150 mg of the USP1 inhibitor or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor in an amount equivalent to about 1150 mg of the USP1 inhibitor. In some embodiments, the medicament is formulated to administer about 1200 mg of the USP1 inhibitor or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor in an amount equivalent to about 1200 mg of the USP1 inhibitor. In some embodiments, the medicament is formulated to administer about 1250 mg of the USP1 inhibitor or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor in an amount equivalent to about 1250 mg of the USP1 inhibitor. In some embodiments, the medicament is formulated to administer about 1300 mg of the USP1 inhibitor or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor in an amount equivalent to about 1300 mg of the USP1 inhibitor. In some embodiments, the medicament is formulated to administer about 1350 mg of the USP1 inhibitor or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor in an amount equivalent to about 1350 mg of the USP1 inhibitor. In some embodiments, the medicament is formulated to administer about 1400 mg of the USP1 inhibitor or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor in an amount equivalent to about 1400 mg of the USP1 inhibitor. In some embodiments, the medicament is formulated to administer about 1450 mg of the USP1 inhibitor or an amount of a salt, solvate, hydrate or cocrystal of the USP1 inhibitor equivalent to about 1450 mg of the USP1 inhibitor. In some embodiments, the medicament is formulated to administer about 1500 mg of the USP1 inhibitor or an amount of a salt, solvate, hydrate or cocrystal of the USP1 inhibitor equivalent to about 1500 mg of the USP1 inhibitor.In some embodiments, the medicament is formulated to administer about 1550 mg of the USP1 inhibitor or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor in an amount equivalent to about 1550 mg of the USP1 inhibitor. In some embodiments, the medicament is formulated to administer about 1600 mg of the USP1 inhibitor or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor in an amount equivalent to about 1600 mg of the USP1 inhibitor. In some embodiments, the medicament is formulated to administer about 1650 mg of the USP1 inhibitor or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor in an amount equivalent to about 1650 mg of the USP1 inhibitor. In some embodiments, the medicament is formulated to administer about 1700 mg of the USP1 inhibitor or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor in an amount equivalent to about 1700 mg of the USP1 inhibitor. In some embodiments, the medicament is formulated to administer about 1750 mg of the USP1 inhibitor or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor in an amount equivalent to about 1750 mg of the USP1 inhibitor. In some embodiments, the medicament is formulated to administer about 1800 mg of the USP1 inhibitor or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor in an amount equivalent to about 1800 mg of the USP1 inhibitor. In some embodiments, the medicament is formulated to administer about 1850 mg of the USP1 inhibitor or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor in an amount equivalent to about 1850 mg of the USP1 inhibitor. In some embodiments, the medicament is formulated to administer about 1900 mg of the USP1 inhibitor or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor in an amount equivalent to about 1900 mg of the USP1 inhibitor. In some embodiments, the medicament is formulated to administer about 1950 mg of the USP1 inhibitor or an amount of a salt, solvate, hydrate or cocrystal of the USP1 inhibitor equivalent to about 1950 mg of the USP1 inhibitor. In some embodiments, the medicament is formulated to administer about 2000 mg of the USP1 inhibitor or an amount of a salt, solvate, hydrate or cocrystal of the USP1 inhibitor equivalent to about 2000 mg of the USP1 inhibitor.In some embodiments, the medicament is formulated to administer about 2100 mg of the USP1 inhibitor or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor in an amount equivalent to about 2100 mg of the USP1 inhibitor. In some embodiments, the medicament is formulated to administer about 2200 mg of the USP1 inhibitor or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor in an amount equivalent to about 2200 mg of the USP1 inhibitor. In some embodiments, the medicament is formulated to administer about 2300 mg of the USP1 inhibitor or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor in an amount equivalent to about 2300 mg of the USP1 inhibitor. In some embodiments, the medicament is formulated to administer about 2400 mg of the USP1 inhibitor or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor in an amount equivalent to about 2400 mg of the USP1 inhibitor. In some embodiments, the medicament is formulated for administration of about 2500 mg of the USP1 inhibitor, or a salt, solvate, hydrate, or cocrystal of the USP1 inhibitor in an amount equivalent to about 2500 mg of the USP1 inhibitor. In some embodiments, the medicament is formulated for administration of about 50 mg to about 2500 mg of the USP1 inhibitor, or a salt, solvate, hydrate, or cocrystal of the USP1 inhibitor in an amount equivalent to about 50 mg to about 2500 mg of the USP1 inhibitor. In some embodiments, the medicament is formulated for administration of about 50 mg to about 2000 mg of the USP1 inhibitor, or a salt, solvate, hydrate, or cocrystal of the USP1 inhibitor in an amount equivalent to about 50 mg to about 200 mg of the USP1 inhibitor. In some embodiments, the medicament is formulated for administration of about 50 mg to about 1500 mg of the USP1 inhibitor, or a salt, solvate, hydrate, or cocrystal of the USP1 inhibitor in an amount equivalent to about 50 mg to about 1500 mg of the USP1 inhibitor. In some embodiments, the medicament is formulated for administration of about 50 mg to about 1000 mg of the USP1 inhibitor, or a salt, solvate, hydrate, or cocrystal of the USP1 inhibitor in an amount equivalent to about 50 mg to about 1000 mg of the USP1 inhibitor.In some embodiments, the medicament is formulated for administration of about 100 mg to about 1000 mg of the USP1 inhibitor, or an amount of a salt, solvate, hydrate, or cocrystal of the USP1 inhibitor equivalent to about 100 mg to about 1000 mg of the USP1 inhibitor. In some embodiments, the medicament is formulated for administration of about 200 mg to about 800 mg of the USP1 inhibitor, or an amount of a salt, solvate, hydrate, or cocrystal of the USP1 inhibitor equivalent to about 200 mg to about 800 mg of the USP1 inhibitor. In some embodiments in the above paragraph, the USP1 inhibitor is Compound I. In some embodiments described in the above paragraph, the USP1 inhibitor is administered as divided doses over the course of a day. For example, in some embodiments, the USP1 inhibitor is administered twice a day (e.g., if the dosage is 1000 mg or an equivalent amount, the USP1 inhibitor is administered in a first dose of 500 mg and a second dose of 500 mg on the same day. g, in which case the first and second doses are not simultaneous. The first and second doses may be the same or different amounts.

[0074] In some embodiments, such medicaments are for administration about once a day. In some embodiments, such medicaments are for administration at least two times (e.g., for two consecutive days). In some embodiments, such medicaments are for administration at least three times (e.g., for three consecutive days). In some embodiments, such medicaments are for administration at least four times (e.g., for four consecutive days). In some embodiments, such medicaments are for administration at least five times (e.g., for five consecutive days). In some embodiments, such medicaments are for administration at least five times (e.g., for five consecutive days). In some embodiments, such medicaments are for administration at least ten times (e.g., for about ten consecutive days). In some embodiments, such medicaments are for administration at least fifteen times (e.g., for about fifteen consecutive days). In some embodiments, such medicaments are for administration at least twenty times (e.g., for about twenty consecutive days). In some embodiments, such medicaments are for administration at least twenty-five times (e.g., for about twenty-five consecutive days). In some embodiments, such medicaments are for administration for about 28 times (e.g., for about 28 consecutive days). In some embodiments, such medicaments are for administration for a period of at least 3 days, or at least 4 days, or at least 5 days, or at least 10 days, or at least 15 days, or at least 20 days, or at least 25 days, or at least 1 month, or at least 2 months, or at least 3 months, or at least 4 months, or at least 5 months, or at least 6 months, or at least 7 months, or at least 8 months, or at least 9 months, or at least 10 months, or at least 11 months, or at least 1 year, or at least 18 months, or at least 2 years, or more.

[0075] In some embodiments, such medicaments are for administration about once every 21 days (about once every 3 weeks). In some embodiments, such medicaments are for administration at least twice (e.g., about 21 days apart). In some embodiments, such medicaments are for administration at least three times (e.g., about 21 days apart). In some embodiments, such medicaments are for administration at least four times (e.g., about 21 days apart). In some embodiments, such medicaments are for administration at least five times (e.g., about 21 days apart).

[0076] In some embodiments, the cancer treated with a USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal thereof) is a solid tumor. In some embodiments, the cancer treated with a USP1 inhibitor is a cancer comprising cancer cells having a mutation in the gene encoding p53. In some embodiments, the cancer treated with a USP1 inhibitor is a cancer comprising cancer cells having a loss-of-function mutation in the gene encoding p53. In some embodiments, the cancer treated with a USP1 inhibitor is a cancer comprising cancer cells having a mutation (somatic and / or germline mutation) in the gene encoding BRCA1. In some embodiments, the cancer treated with a USP1 inhibitor is a cancer comprising cancer cells having a mutation (somatic and / or germline mutation) in the gene encoding BRCA2. In some embodiments, the cancer treated with a USP1 inhibitor is a cancer comprising cancer cells having a loss-of-function mutation in the gene encoding ATM.

[0077] In some embodiments, the cancer treated with the USP1 inhibitor is selected from lung cancer (including non-small cell lung cancer (NSCLC)), colon cancer, bladder cancer, osteosarcoma, ovarian cancer, skin cancer, and breast cancer. In some embodiments, the cancer treated with the USP1 inhibitor is selected from lung cancer, non-small cell lung cancer (NSCLC), osteosarcoma, ovarian cancer, and breast cancer. In some embodiments, the cancer is ovarian cancer or breast cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the ovarian cancer is serous ovarian cancer. In some embodiments, the ovarian cancer has previously been treated with platinum-based chemotherapy. In some embodiments, the ovarian cancer is platinum-resistant. In some embodiments, the ovarian cancer is platinum-sensitive. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is triple-negative breast cancer. In some embodiments, the breast cancer is human epidermal growth factor receptor 2 (HER2) negative. In some embodiments, breast cancer is germline breast cancer susceptibility gene mutation (gBRCAm) breast cancer.As used herein, gBRCAm breast cancer refers to breast cancer with documented mutations in BRCA1 or BRCA2 that are predicted or suspected to be harmful (known or predicted to be harmful / lead to loss of function).In some embodiments, breast cancer is metastatic breast cancer.

[0078] In some embodiments, the cancer treated with the USP1 inhibitor is selected from the group consisting of bone cancer, including osteosarcoma and chondrosarcoma; brain cancer, including glioma, glioblastoma, astrocytoma, medulloblastoma and meningioma; soft tissue cancer, including rhabdoid and sarcoma; renal cancer; bladder cancer; skin cancer, including melanoma; and lung cancer, including non-small cell lung cancer; colon cancer, uterine cancer; nervous system cancer; head and neck cancer; pancreatic cancer; and cervical cancer.

[0079] In some embodiments, the cancer is a recurrent cancer. In some embodiments, the cancer treated with the USP1 inhibitor has been previously treated with a PARP inhibitor (PARPi). In some embodiments, the cancer treated with the USP1 inhibitor has been previously treated with at least one systemic chemotherapy for metastatic disease.

[0080] In some embodiments, the cancer treated with USP1 inhibitor comprises cancer cells with elevated levels of RAD18. In some embodiments, the elevated level of RAD18 is elevated RAD18 protein level. In some embodiments, the elevated level of RAD18 is elevated RAD18 mRNA level. In some embodiments, the elevated level of RAD18 (e.g., RAD18 protein and / or RAD18 mRNA) is detected before administration (e.g., in a cancer sample obtained from a subject). That is, in some embodiments, the cancer of the subject is tested for RAD18 protein or mRNA before starting treatment with USP1 inhibitor.

[0081] In some embodiments, the cancer treated with USP1 inhibitor is the cancer that comprises cancer cells with elevated levels of RAD51. The elevated level of RAD51 can be elevated RAD51 protein level, elevated RAD51 protein focus level, and / or elevated RAD51 mRNA level. In some embodiments, the cancer that comprises cancer cells with elevated levels of RAD51 refers to a cancer in which at least 10% of the cells in cell cycle S / G2 phase (e.g., geminin-positive cells) in a sample obtained from the cancer are RAD51 positive (e.g., contain 5 or more RAD51 nuclear foci).

[0082] The cancer with elevated RAD51 level can be homologous recombination deficient cancer.The cancer with elevated RAD51 level can be BRCA1 mutation cancer, BRCA2 mutation cancer, or BRCA1 and BRCA2 mutation cancer.The cancer with elevated RAD51 level can be cancer with harmful or suspected harmful mutation in BRCA1 and BRCA2 genes, and / or cancer with positive genomic instability score, for example, as determined by using myChoice® CDx (Myriad®).

[0083] Cancers having cells with elevated levels of RAD51 are sometimes referred to herein as "RAD51 high cancers."

[0084] RAD51 protein level can be detected, for example, by immunofluorescence, Western blot, fluorescence-activated cell sorting (FACS), and / or immunohistochemistry.RAD51 mRNA level can be detected, for example, by quantitative reverse transcriptase (RT)-polymerase chain reaction (PCR).Elevated levels of RAD51 protein and / or mRNA indicate that cancer is sensitive to USP1 inhibitors.

[0085] Methods for detecting RAD51 and RAD51 protein foci are provided, for example, in Castroviejo-Bermejo, Marta, et al., EMBO Molecular Medicine 10(12):e9172 (2018), which is incorporated by reference in its entirety. RAD51 can be detected, for example, using immunofluorescence. RAD51 foci, for example, 0.42-1.15 μm in diameter, can be quantified in formalin-fixed paraffin-embedded (FFPE) tumor samples by scoring the percentage of cells in the S / G2 phase of the cell cycle (e.g., geminin-positive cells) that have 5 or more RAD51 nuclear foci. In some embodiments, a cancer comprising cells with elevated levels of RAD51 is a cancer in which at least 10% of cells in the S / G2 phase of the cell cycle (e.g., geminin-positive cells) are RAD51 positive.

[0086] In some embodiments, USP1 inhibitors are used to treat cancers that are homologous recombination deficient cancers. In some embodiments, USP1 inhibitors are used to treat cancers that include cancer cells that have a mutation in the gene encoding p53. In some embodiments, USP1 inhibitors are used to treat cancers that include cancer cells that have a loss-of-function mutation in the gene encoding p53. In some embodiments, USP1 inhibitors are used to treat cancers that do not have a defect in the homologous recombination pathway.

[0087] In some embodiments, the USP1 inhibitor is used to treat a cancer that is a BRCA1 (somatic or germline) mutated cancer. In some embodiments, the USP1 inhibitor is used to treat a cancer that is a BRCA2 (somatic or germline) mutated cancer. In some embodiments, the USP1 inhibitor is used to treat a cancer that is a BRCA1 (somatic or germline) mutated cancer and a BRCA2 (somatic or germline) mutated cancer. In some embodiments, the cancer is not a BRCA1 mutated cancer or a BRCA2 mutated cancer. In some embodiments, the cancer is a BRCA1 deficient cancer. In some embodiments, the cancer is a BRCA2 deficient cancer. In some embodiments, the cancer is a BRCA1 deficient cancer and a BRCA2 deficient cancer.

[0088] In some embodiments, the USP1 inhibitor is used to treat a cancer that is an ATM mutant cancer. In some embodiments, the cancer is not an ATM mutant cancer. In some embodiments, the cancer is an ATM deficient cancer.

[0089] In some embodiments, USP1 inhibitors are used to treat cancers that are PARP inhibitor-resistant or refractory cancers. In some embodiments, USP1 inhibitors are used to treat cancers that are PARP inhibitor-resistant or refractory BRCA1-deficient cancers.

[0090] In some embodiments, the cancer is a BRCA1 and / or BRCA2 mutated cancer, and the cancer comprises cells with elevated levels of RAD18, e.g., the elevated levels of RAD18 are at least as high as RAD18 protein and / or mRNA levels in ES2 cells, or the elevated levels of RAD18 are higher than RAD18 protein and / or mRNA levels in HEP3B217 cells. In some embodiments, the triple-negative breast cancer is a BRCA1 and / or BRCA2 mutated cancer.

[0091] In some embodiments, the cancer is a solid cancer. In some embodiments, the cancer is a DNA damage repair pathway deficient cancer. In some embodiments, the cancer is a homologous recombination deficient cancer. In some embodiments, the cancer comprises cancer cells with a mutation in a gene encoding p53. In some embodiments, the cancer comprises cancer cells with a loss-of-function mutation in a gene encoding p53. In some embodiments, the cancer is selected from the group consisting of non-small cell lung cancer (NSCLC), ovarian cancer, and breast cancer (including triple-negative breast cancer). In some embodiments, the cancer is ovarian cancer or breast cancer (including triple-negative breast cancer). In some embodiments, the cancer is ovarian cancer (including serous ovarian cancer). In some embodiments, the ovarian cancer has previously been treated with platinum-based chemotherapy. In some embodiments, the ovarian cancer is platinum-resistant. In some embodiments, the cancer is breast cancer (including triple-negative breast cancer). In some embodiments, the breast cancer is human epidermal growth factor receptor 2 (HER2) negative. In some embodiments, the breast cancer is germline breast cancer susceptibility gene mutation (gBRCAm) breast cancer. In some embodiments, the breast cancer is metastatic breast cancer.

[0092] III. USP1 Inhibitors USP1 inhibitors are disclosed, for example, in WO 2020 / 132269 and PCT / US2021 / 057072, each of which is incorporated herein by reference in its entirety. In some embodiments provided herein, the USP1 inhibitor is 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, or "Compound I." [ka] or a pharma- ceutically acceptable salt, solvate, hydrate or co-crystal thereof.

[0093] In some embodiments, the USP1 inhibitor is a compound of formula (I) or its pharma- ceutically acceptable salt, solvate, hydrate or cocrystal in solid state form.In some embodiments, the solid state form is the amorphous form of the compound of formula (I).In some embodiments, the amorphous form is its hydrate, anhydrous or solvate.In some embodiments, the amorphous form is substantially free of other polymorphic forms.

[0094] In some embodiments, the USP1 inhibitor comprises a mixture that contains a majority of amorphous form compared to other solid state forms of the compound of formula (I). In some embodiments, the amorphous form has a polymorphic purity of at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%.

[0095] In some embodiments, the solid state form is a crystalline form of the compound of formula (I). In some embodiments, the crystalline form is a hydrate, anhydrate, or solvate thereof. In some embodiments, the solvate is a dichloromethane solvate.

[0096] In some embodiments, the USP1 inhibitor is a compound of formula (I) in the solid state form of crystalline form A, characterized by an XRPD pattern having peaks at 14.3±0.2, 21.5±0.2, and 21.8±0.2 degrees 2θ.

[0097] The following section describes identified solid state forms of the compound of formula (I) and selected properties of these solid state forms.

[0098] A. Crystal form A In some embodiments, the USP1 inhibitor for the uses and methods provided herein is 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine of formula (I) in crystalline form A.

[0099] In some embodiments, the crystalline form A is 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine hydrate.

[0100] In some embodiments, the melting point of crystalline form A is about 165°C.

[0101] In some embodiments, crystalline form A is characterized by an XRPD pattern with peaks at 14.3±0.2, 21.5±0.2, and 21.8±0.2 degrees 2θ as measured by CuKα radiation. In some embodiments, crystalline form A is characterized by an XRPD pattern with peaks at 7.1±0.2, 14.3±0.2, 21.5±0.2, and 21.8±0.2 degrees 2θ as measured by CuKα radiation. In some embodiments, crystalline form A is characterized by an XRPD pattern with peaks at 7.1±0.2, 14.3±0.2, 19.1±0.2, 21.5±0.2, and 21.8±0.2 degrees 2θ as measured by CuKα radiation. In some embodiments, crystalline form A is characterized by an XRPD pattern with peaks at 7.1±0.2, 14.3±0.2, 15.2±0.2, 19.1±0.2, 21.5±0.2, and 21.8±0.2 degrees 2θ as measured with CuKα radiation.

[0102] In some embodiments, crystalline form A is characterized by an XRPD pattern substantially as shown in FIG.

[0103] In some embodiments, crystalline Form A is characterized by 3 or more, 4 or more, 5 or more, or 6 or more XRPD peaks listed in Table 1(a and b) below. [Table 1a] [Table 1b]

[0104] In some embodiments, crystalline form A is characterized by an endothermic peak at about 162° C. to about 168° C., or about 163° C. to about 167° C., or about 164° C. to about 166° C., as determined by DSC. In some embodiments, crystalline form A is characterized by an endothermic peak at about 165° C., as determined by DSC.

[0105] In some embodiments, crystalline form A is characterized by a DSC profile substantially as shown in FIG.

[0106] In some embodiments, crystalline form A is characterized by a loss of about 0.88 wt% to about 0.98 wt% between room temperature and about 150° C. In some embodiments, crystalline form A is characterized by a loss of about 0.90 wt% to about 0.96 wt% between room temperature and about 150° C. In some embodiments, crystalline form A is characterized by a loss of about 0.93 wt% between room temperature and about 150° C.

[0107] In some embodiments, crystalline form A is characterized by a TGA profile substantially as shown in FIG.

[0108] In some embodiments, crystalline form A is characterized by at least two of the following: a) the XRPD pattern depicted in FIG. 1; b) the DSC profile depicted in FIG. 2; or c) the TGA profile depicted in FIG.

[0109] In some embodiments, crystalline form A has a unit cell that is indicative of being monoclinic.

[0110] In some embodiments, crystalline form A has a unit cell with an a value of about 12.054 Å, a b value of about 8.775 Å, and a c value of about 24.837 Å. In some embodiments, form A has a volume of about 2603.68 Å. 3 The unit cell is

[0111] In some embodiments, crystalline form A is substantially free of other polymorphic forms. In some embodiments, crystalline form A has a polymorphic purity of at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%. In some embodiments, crystalline form A has a polymorphic purity of at least 80%.

[0112] In another embodiment, the present disclosure relates to a mixture comprising crystalline Form A and a second solid state form of the compound of formula (I). In some embodiments, the second solid state form of the compound of formula (I) is crystalline Form 2.

[0113] In some embodiments, the present disclosure relates to mixtures comprising a majority of crystalline Form A as compared to other solid state forms of the compound of formula (I).

[0114] B. Crystal form 2 In some embodiments, the USP1 inhibitor for the uses and methods provided herein is a solid state form that is a pharma- ceutically acceptable salt of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine of formula (I). In some embodiments, the pharma-ceutically acceptable salt is formed between 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine of formula (I) and a pharma-ceutically acceptable acid. In some embodiments, the pharma-ceutically acceptable acid is gentisic acid.

[0115] In some embodiments, the USP1 inhibitor is the gentisate salt of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine of formula (I) in amorphous form. In some embodiments, the amorphous form is substantially free of other polymorphic forms. In some embodiments, the amorphous form has a polymorphic purity of at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%.

[0116] In some embodiments, the USP1 inhibitor is the gentisate salt of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine of formula (I) in co-crystal form.

[0117] In some embodiments, the USP1 inhibitor is a 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine of formula (I) and a second pharma- ceutically acceptable compound, in the form of a solid-state gentisate cocrystal. The pharma- ceutically acceptable cocrystal is formed between 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine of formula (I) and gentisic acid.

[0118] In some embodiments, the gentisic acid co-crystal is crystalline form 2, characterized by an XRPD pattern with peaks at 16.6±0.2, 18.7±0.2, and 22.5±0.2 degrees 2θ.

[0119] In some embodiments, crystalline Form 2 is anhydrous.

[0120] In some embodiments, the melting point of crystalline form 2 is about 184° C. to about 190° C. In some embodiments, the melting point of crystalline form 2 is about 186° C. to about 188° C. In some embodiments, the melting point of crystalline form 2 is about 187° C.

[0121] In some embodiments, crystalline form 2 is characterized by an XRPD pattern with peaks at 16.6±0.2, 18.7±0.2, and 22.5±0.2 degrees 2θ as measured by CuKα radiation. In another embodiment, crystalline form 2 is characterized by an XRPD pattern with peaks at 16.6±0.2, 18.7±0.2, 22.3±0.2, and 22.5±0.2 degrees 2θ as measured by CuKα radiation. In some embodiments, crystalline form 2 is characterized by an XRPD pattern with peaks at 16.6±0.2, 18.7±0.2, 22.3±0.2, 22.5±0.2, and 26.0±0.2 degrees 2θ as measured by CuKα radiation. In some embodiments, crystalline Form 2 is characterized by an XRPD pattern having peaks at 16.6±0.2, 18.7±0.2, 20.8±0.2, 22.3±0.2, 22.5±0.2, and 26.0±0.2 degrees 2θ as measured with CuKα radiation.

[0122] In some embodiments, crystalline Form 2 is characterized by an XRPD pattern substantially as shown in Figure 4. In some embodiments, crystalline Form 2 is characterized by 3 or more, 4 or more, 5 or more, or 6 or more XRPD peaks listed in Table 2(a and b) below. [Table 2a] [Table 2b]

[0123] In some embodiments, crystalline Form 2 is characterized by an endothermic peak at about 181° C. to about 191° C., or about 183° C. to about 189° C., or about 185° C. to about 187° C., as determined by DSC. In some embodiments, crystalline Form 2 is characterized by an endothermic peak at about 186.0° C., as determined by DSC.

[0124] In some embodiments, crystalline Form 2 is characterized by a DSC profile substantially as shown in FIG.

[0125] In some embodiments, crystalline form 2 is characterized by a loss of about 2.5 wt % to about 3.5 wt % between room temperature and about 170° C. In some embodiments, crystalline form 2 is characterized by a loss of about 3.0 wt % to about 3.4 wt % between room temperature and about 170° C. In some embodiments, crystalline form 2 is characterized by a loss of about 3.17 wt % between room temperature and about 170° C.

[0126] In some embodiments, crystalline Form 2 is characterized by a TGA profile substantially as shown in FIG.

[0127] In some embodiments, crystalline Form 2 is characterized by at least two of the following: a) the XRPD pattern depicted in FIG. 4; b) the DSC profile depicted in FIG. 5; or c) the TGA profile depicted in FIG. 5.

[0128] In some embodiments, crystalline Form 2 has a unit cell that is indicative of being monoclinic.

[0129] In some embodiments, crystalline Form 2 has a unit cell with an a value of about 11.113 Å, a b value of about 12.356 Å, and a c value of about 24.048 Å. In some embodiments, Form 2 has a volume of about 3223.93 Å. 3 The unit cell is

[0130] The unit cell parameters of crystalline form 2 are shown in Table 3. [Table 3]

[0131] In some embodiments, crystalline Form 2 is substantially free of other polymorphic forms. In some embodiments, crystalline Form 2 has a polymorphic purity of at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%.

[0132] In some embodiments, the USP1 inhibitor comprises a mixture comprising crystalline form 2 and a second solid state form of the compound of formula (I). In some embodiments, the second solid state form of the compound of formula (I) is crystalline form A. In some embodiments, the USP1 inhibitor comprises a mixture comprising a majority of crystalline form 2 compared to other solid state forms of the compound of formula (I).

[0133] Crystalline Form 2 exhibits unexpected chemical and physical properties and exhibits favorable bioavailability properties compared to the free base form. In particular, as shown in Figure 6, 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine of formula (I) and gentisic acid exhibit significant hydrogen bonding interactions, albeit interactions between a weak base and a weak acid, respectively.

[0134] Additionally, as shown in Example 3, crystalline Form 2 surprisingly exhibits higher mouse oral exposure levels compared to other solid state forms of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine of formula (I). For example, as shown in Example 1, in some embodiments, crystalline Form 2 (gentisic acid co-crystal) exhibits higher exposure levels than crystalline Form A (free base) at about 300 mg / kg.

[0135] III. Pharmaceutical Compositions and Kits As provided herein, USP1 inhibitor (e.g., compound I or its pharma- ceutically acceptable salt, solvate, hydrate or cocrystal) can be present in pharmaceutical compositions, including any compositions in which the inhibitor is combined with one or more pharma- ceutically acceptable carriers.In some embodiments, the USP1 inhibitor is present in the composition in an amount effective to achieve the intended therapeutic purpose.

[0136] In some embodiments, the pharmaceutical composition comprises about 75 mg to about 1000 mg of a USP1 inhibitor (e.g., Compound I), or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal thereof, in an amount equivalent to about 75 mg to about 1000 mg of the USP1 inhibitor. In some embodiments, the pharmaceutical composition comprises about 75 mg of a USP1 inhibitor (e.g., Compound I), or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal thereof, in an amount equivalent to about 75 mg of the USP1 inhibitor. In some embodiments, the pharmaceutical composition comprises about 100 mg of a USP1 inhibitor (e.g., Compound I), or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal thereof, in an amount equivalent to about 100 mg of the USP1 inhibitor. In some embodiments, the pharmaceutical composition comprises about 150 mg of a USP1 inhibitor (e.g., Compound I), or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal thereof, in an amount equivalent to about 150 mg of the USP1 inhibitor. In some embodiments, the pharmaceutical composition comprises about 200 mg of a USP1 inhibitor (e.g., compound I) or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal thereof in an amount equivalent to about 200 mg of the USP1 inhibitor. In some embodiments, the pharmaceutical composition comprises about 250 mg of a USP1 inhibitor (e.g., compound I) or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal thereof in an amount equivalent to about 250 mg of the USP1 inhibitor. In some embodiments, the pharmaceutical composition comprises about 300 mg of a USP1 inhibitor (e.g., compound I) or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal thereof in an amount equivalent to about 300 mg of the USP1 inhibitor. In some embodiments, the pharmaceutical composition comprises about 350 mg of a USP1 inhibitor (e.g., compound I) or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal thereof in an amount equivalent to about 350 mg of the USP1 inhibitor. In some embodiments, the pharmaceutical composition comprises about 400 mg of a USP1 inhibitor (e.g., Compound I), or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal thereof, equivalent to about 400 mg of the USP1 inhibitor. In some embodiments, the pharmaceutical composition comprises about 450 mg of a USP1 inhibitor (e.g., Compound I), or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal thereof, equivalent to about 450 mg of the USP1 inhibitor.In some embodiments, the pharmaceutical composition comprises about 500 mg of a USP1 inhibitor (e.g., compound I) or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal thereof in an amount equivalent to about 500 mg of the USP1 inhibitor. In some embodiments, the pharmaceutical composition comprises about 550 mg of a USP1 inhibitor (e.g., compound I) or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal thereof in an amount equivalent to about 550 mg of the USP1 inhibitor. In some embodiments, the pharmaceutical composition comprises about 600 mg of a USP1 inhibitor (e.g., compound I) or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal thereof in an amount equivalent to about 600 mg of the USP1 inhibitor. In some embodiments, the pharmaceutical composition comprises about 650 mg of a USP1 inhibitor (e.g., compound I) or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal thereof in an amount equivalent to about 650 mg of the USP1 inhibitor. In some embodiments, the pharmaceutical composition comprises about 700 mg of a USP1 inhibitor (e.g., compound I) or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal thereof in an amount equivalent to about 700 mg of the USP1 inhibitor. In some embodiments, the pharmaceutical composition comprises about 750 mg of a USP1 inhibitor (e.g., compound I) or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal thereof in an amount equivalent to about 750 mg of the USP1 inhibitor. In some embodiments, the pharmaceutical composition comprises about 800 mg of a USP1 inhibitor (e.g., compound I) or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal thereof in an amount equivalent to about 800 mg of the USP1 inhibitor. In some embodiments, the pharmaceutical composition comprises about 850 mg of a USP1 inhibitor (e.g., compound I) or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal thereof in an amount equivalent to about 850 mg of the USP1 inhibitor. In some embodiments, the pharmaceutical composition comprises about 900 mg of a USP1 inhibitor (e.g., Compound I), or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal thereof, equivalent to about 900 mg of the USP1 inhibitor. In some embodiments, the pharmaceutical composition comprises about 950 mg of a USP1 inhibitor (e.g., Compound I), or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal thereof, equivalent to about 950 mg of the USP1 inhibitor.In some embodiments, the pharmaceutical composition comprises about 1000 mg of a USP1 inhibitor (e.g., compound I) or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal thereof in an amount equivalent to about 1000 mg of the USP1 inhibitor. In some embodiments, the pharmaceutical composition comprises about 1050 mg of a USP1 inhibitor (e.g., compound I) or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal thereof in an amount equivalent to about 1050 mg of the USP1 inhibitor. In some embodiments, the pharmaceutical composition comprises about 1100 mg of a USP1 inhibitor (e.g., compound I) or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal thereof in an amount equivalent to about 1100 mg of the USP1 inhibitor. In some embodiments, the pharmaceutical composition comprises about 1150 mg of a USP1 inhibitor (e.g., compound I) or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal thereof in an amount equivalent to about 1150 mg of the USP1 inhibitor. In some embodiments, the pharmaceutical composition comprises about 1200 mg of a USP1 inhibitor (e.g., compound I) or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal thereof in an amount equivalent to about 1200 mg of the USP1 inhibitor. In some embodiments, the pharmaceutical composition comprises about 1250 mg of a USP1 inhibitor (e.g., compound I) or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal thereof in an amount equivalent to about 1250 mg of the USP1 inhibitor. In some embodiments, the pharmaceutical composition comprises about 1300 mg of a USP1 inhibitor (e.g., compound I) or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal thereof in an amount equivalent to about 1300 mg of the USP1 inhibitor. In some embodiments, the pharmaceutical composition comprises about 1350 mg of a USP1 inhibitor (e.g., compound I) or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal thereof in an amount equivalent to about 1350 mg of the USP1 inhibitor. In some embodiments, the pharmaceutical composition comprises about 1400 mg of a USP1 inhibitor (e.g., Compound I), or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal thereof, equivalent to about 1400 mg of the USP1 inhibitor. In some embodiments, the pharmaceutical composition comprises about 1450 mg of a USP1 inhibitor (e.g., Compound I), or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal thereof, equivalent to about 1450 mg of the USP1 inhibitor.In some embodiments, the pharmaceutical composition comprises about 1500 mg of a USP1 inhibitor (e.g., compound I) or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal thereof in an amount equivalent to about 1500 mg of the USP1 inhibitor. In some embodiments, the pharmaceutical composition comprises about 1550 mg of a USP1 inhibitor (e.g., compound I) or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal thereof in an amount equivalent to about 1550 mg of the USP1 inhibitor. In some embodiments, the pharmaceutical composition comprises about 1600 mg of a USP1 inhibitor (e.g., compound I) or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal thereof in an amount equivalent to about 1600 mg of the USP1 inhibitor. In some embodiments, the pharmaceutical composition comprises about 1650 mg of a USP1 inhibitor (e.g., compound I) or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal thereof in an amount equivalent to about 1650 mg of the USP1 inhibitor. In some embodiments, the pharmaceutical composition comprises about 1700 mg of a USP1 inhibitor (e.g., compound I) or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal thereof in an amount equivalent to about 1700 mg of the USP1 inhibitor. In some embodiments, the pharmaceutical composition comprises about 1750 mg of a USP1 inhibitor (e.g., compound I) or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal thereof in an amount equivalent to about 1750 mg of the USP1 inhibitor. In some embodiments, the pharmaceutical composition comprises about 1800 mg of a USP1 inhibitor (e.g., compound I) or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal thereof in an amount equivalent to about 1800 mg of the USP1 inhibitor. In some embodiments, the pharmaceutical composition comprises about 1850 mg of a USP1 inhibitor (e.g., compound I) or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal thereof in an amount equivalent to about 1850 mg of the USP1 inhibitor. In some embodiments, the pharmaceutical composition comprises about 1900 mg of a USP1 inhibitor (e.g., Compound I), or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal thereof, equivalent to about 1900 mg of the USP1 inhibitor. In some embodiments, the pharmaceutical composition comprises about 1950 mg of a USP1 inhibitor (e.g., Compound I), or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal thereof, equivalent to about 1950 mg of the USP1 inhibitor.In some embodiments, the pharmaceutical composition comprises about 2000 mg of a USP1 inhibitor (e.g., compound I) or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal thereof in an amount equivalent to about 2000 mg of the USP1 inhibitor. In some embodiments, the pharmaceutical composition comprises about 2100 mg of a USP1 inhibitor (e.g., compound I) or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal thereof in an amount equivalent to about 2100 mg of the USP1 inhibitor. In some embodiments, the pharmaceutical composition comprises about 2200 mg of a USP1 inhibitor (e.g., compound I) or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal thereof in an amount equivalent to about 2200 mg of the USP1 inhibitor. In some embodiments, the pharmaceutical composition comprises about 2300 mg of a USP1 inhibitor (e.g., compound I) or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal thereof in an amount equivalent to about 2300 mg of the USP1 inhibitor. In some embodiments, the pharmaceutical composition comprises about 2400 mg of a USP1 inhibitor (e.g., Compound I), or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal thereof, equivalent to about 2400 mg of the USP1 inhibitor. In some embodiments, the pharmaceutical composition comprises about 2500 mg of a USP1 inhibitor (e.g., Compound I), or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal thereof, equivalent to about 2500 mg of the USP1 inhibitor.

[0137] In some embodiments, the pharmaceutical composition contains about 50 mg to about 2500 mg of the USP1 inhibitor, or a salt, solvate, hydrate, or cocrystal thereof in an amount equivalent to about 50 mg to about 2500 mg of the USP1 inhibitor. In some embodiments, the pharmaceutical composition contains about 50 mg to about 2000 mg of the USP1 inhibitor, or a salt, solvate, hydrate, or cocrystal thereof in an amount equivalent to about 50 mg to about 200 mg of the USP1 inhibitor. In some embodiments, the pharmaceutical composition contains about 50 mg to about 1500 mg of the USP1 inhibitor, or a salt, solvate, hydrate, or cocrystal thereof in an amount equivalent to about 50 mg to about 1500 mg of the USP1 inhibitor. In some embodiments, the pharmaceutical composition contains about 50 mg to about 1000 mg of the USP1 inhibitor, or a salt, solvate, hydrate, or cocrystal thereof in an amount equivalent to about 50 mg to about 1000 mg of the USP1 inhibitor. In some embodiments, the pharmaceutical composition comprises about 100 mg to about 1000 mg of a USP1 inhibitor, or a salt, solvate, hydrate, or cocrystal thereof in an amount equivalent to about 100 mg to about 1000 mg of the USP1 inhibitor. In some embodiments, the pharmaceutical composition comprises about 200 mg to about 800 mg of a USP1 inhibitor, or a salt, solvate, hydrate, or cocrystal thereof in an amount equivalent to about 200 mg to about 800 mg of the USP1 inhibitor. In some embodiments in the above paragraph, the USP1 inhibitor is Compound I.

[0138] In some embodiments, the pharmaceutical composition comprises about 75 mg to about 1000 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal). In some embodiments, the pharmaceutical composition comprises about 75 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal). In some embodiments, the pharmaceutical composition comprises about 100 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal). In some embodiments, the pharmaceutical composition comprises about 150 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal). In some embodiments, the pharmaceutical composition comprises about 200 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal). In some embodiments, the pharmaceutical composition comprises about 250 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal). In some embodiments, the pharmaceutical composition comprises about 300 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal). In some embodiments, the pharmaceutical composition comprises about 350 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal). In some embodiments, the pharmaceutical composition comprises about 400 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal). In some embodiments, the pharmaceutical composition comprises about 450 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal). In some embodiments, the pharmaceutical composition comprises about 500 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal). In some embodiments, the pharmaceutical composition comprises about 550 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal). In some embodiments, the pharmaceutical composition comprises about 600 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal).In some embodiments, the pharmaceutical composition comprises about 650 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal). In some embodiments, the pharmaceutical composition comprises about 700 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal). In some embodiments, the pharmaceutical composition comprises about 750 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal). In some embodiments, the pharmaceutical composition comprises about 800 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal). In some embodiments, the pharmaceutical composition comprises about 850 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal). In some embodiments, the pharmaceutical composition comprises about 900 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal). In some embodiments, the pharmaceutical composition comprises about 950 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal). In some embodiments, the pharmaceutical composition comprises about 1000 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal). In some embodiments, the pharmaceutical composition comprises about 1050 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal). In some embodiments, the pharmaceutical composition comprises about 1100 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal). In some embodiments, the pharmaceutical composition comprises about 1150 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal). In some embodiments, the pharmaceutical composition comprises about 1200 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal). In some embodiments, the pharmaceutical composition comprises about 1250 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal).In some embodiments, the pharmaceutical composition comprises about 1300 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal). In some embodiments, the pharmaceutical composition comprises about 1350 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal). In some embodiments, the pharmaceutical composition comprises about 1400 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal). In some embodiments, the pharmaceutical composition comprises about 1450 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal). In some embodiments, the pharmaceutical composition comprises about 1500 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal). In some embodiments, the pharmaceutical composition comprises about 1550 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal). In some embodiments, the pharmaceutical composition comprises about 1600 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal). In some embodiments, the pharmaceutical composition comprises about 1650 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal). In some embodiments, the pharmaceutical composition comprises about 1700 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal). In some embodiments, the pharmaceutical composition comprises about 1750 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal). In some embodiments, the pharmaceutical composition comprises about 1800 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal). In some embodiments, the pharmaceutical composition comprises about 1850 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal). In some embodiments, the pharmaceutical composition comprises about 1900 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal).In some embodiments, the pharmaceutical composition comprises about 1950 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal). In some embodiments, the pharmaceutical composition comprises about 2000 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal). In some embodiments, the pharmaceutical composition comprises about 2100 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal). In some embodiments, the pharmaceutical composition comprises about 2200 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal). In some embodiments, the pharmaceutical composition comprises about 2300 mg of the USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate or cocrystal). In some embodiments, the pharmaceutical composition comprises about 2400 mg of a USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal thereof). In some embodiments, the pharmaceutical composition comprises about 2500 mg of a USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal thereof).

[0139] In some embodiments, such medicaments are for administration about once a day. In some embodiments, such medicaments are for administration at least two times (e.g., for two consecutive days). In some embodiments, such medicaments are for administration at least three times (e.g., for three consecutive days). In some embodiments, such medicaments are for administration at least four times (e.g., for four consecutive days). In some embodiments, such medicaments are for administration at least five times (e.g., for five consecutive days). In some embodiments, such medicaments are for administration at least five times (e.g., for five consecutive days). In some embodiments, such medicaments are for administration at least ten times (e.g., for about ten consecutive days). In some embodiments, such medicaments are for administration at least fifteen times (e.g., for about fifteen consecutive days). In some embodiments, such medicaments are for administration at least twenty times (e.g., for about twenty consecutive days). In some embodiments, such medicaments are for administration at least twenty-five times (e.g., for about twenty-five consecutive days). In some embodiments, such medicaments are for administration for about 28 times (e.g., for about 28 consecutive days). In some embodiments, such medicaments are for administration for a period of at least 3 days, or at least 4 days, or at least 5 days, or at least 10 days, or at least 15 days, or at least 20 days, or at least 25 days, or at least 1 month, or at least 2 months, or at least 3 months, or at least 4 months, or at least 5 months, or at least 6 months, or at least 7 months, or at least 8 months, or at least 9 months, or at least 10 months, or at least 11 months, or at least 1 year, or at least 18 months, or at least 2 years, or more.

[0140] In some embodiments, the pharmaceutical composition is for administration about once every 21 days (about once every 3 weeks). In some embodiments, the pharmaceutical composition is for administration at least twice (e.g., about 21 days apart). In some embodiments, the pharmaceutical composition is for administration at least three times (e.g., about 21 days apart). In some embodiments, the pharmaceutical composition is for administration at least four times (e.g., about 21 days apart). In some embodiments, the pharmaceutical composition is for administration at least five times (e.g., about 21 days apart).

[0141] USP1 inhibitor (e.g., Compound I or its pharmaceutically acceptable salt, solvate, hydrate or cocrystal) can be administered to a subject in the form of raw chemical without any other components, but the USP1 inhibitor can also be administered as part of a pharmaceutical composition that contains the inhibitor in combination with a suitable pharmaceutically acceptable carrier (see, for example, Gennaro, Remington: The Science and Practice of Pharmacy with Facts and Comparisons: Drugfacts Plus, 20th ed. (2003); Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed., Lippencott Williams and Wilkins (2004); Kibbe et al., Handbook of Pharmaceutical Excipients, 3rd ed., Pharmaceutical Press (2000)). Such carriers can be selected from pharmaceutically acceptable excipients and auxiliary agents. The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable vehicle" includes any of standard pharmaceutical carriers, solvents, surfactants or vehicles. Standard pharmaceutical carriers and their formulation are described in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 19th ed. 1995.

[0142] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a USP1 inhibitor (e.g., Compound I or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal thereof) and a pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises a gentisic acid cocrystal of the compound of formula (I) in crystalline form 2.

[0143] The pharmaceutical compositions of the present disclosure may be orally administered in any orally acceptable dosage form, including, for example, a capsule, a tablet, an aqueous suspension or solution. In some embodiments, the capsule is a gelatin capsule.

[0144] For oral administration, known carriers can be included in the pharmaceutical composition. For example, microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine can be used with various disintegrating agents such as starch (preferably corn starch, potato starch or tapioca starch), methylcellulose, alginic acid and certain complex silicates, and can be included in tablets with granulating binders such as polyvinylpyrrolidone, sucrose, gelatin and acacia. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate, talc, etc. are often useful for tableting purposes. Similar types of solid compositions can also be used as fillers for gelatin capsules. Preferred materials in this regard include lactose or milk sugar, and high molecular weight polyethylene glycols. When aqueous suspensions and / or elixirs are desired for oral administration, the active ingredient can be combined with various sweeteners or flavoring agents, colorants or dyes, and optionally emulsifying and / or suspending agents, along with diluents such as water, ethanol, propylene glycol, glycerin and various combinations thereof. .

[0145] Pharmaceutical compositions to be used for in vivo administration can be sterile, which is readily accomplished by, for example, filtration through sterile filtration membranes.

[0146] Pharmaceutical compositions within the scope of the present disclosure include any composition in which the USP1 inhibitor is combined with one or more pharma- ceutically acceptable carriers. In some embodiments, the USP1 inhibitor is present in the composition in an amount effective to achieve its intended therapeutic purpose.

[0147] The pharmaceutical composition of the present disclosure can be administered to patients who can experience the beneficial effects of the compounds of the present disclosure.The most important of such patients are mammals, such as humans and companion animals, although the present disclosure is not intended to be so limited.In some embodiments, the patient is a human.In some embodiments, the pharmaceutical composition of the present disclosure can be administered to patients with PARP inhibitor-resistant or refractory cancer.In some embodiments, the pharmaceutical composition of the present disclosure can be administered to patients with PARP inhibitor-resistant or refractory BRCA1-deficient cancer.

[0148] In some embodiments, the present disclosure provides a kit comprising a USP1 inhibitor (e.g., Compound I or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal thereof), or a pharmaceutical composition comprising the same, packaged to facilitate use for carrying out the methods of the present disclosure. In some embodiments, the kit comprises a USP1 inhibitor packaged in a container, such as a sealed bottle or vessel, and a label describing the use of the USP1 inhibitor or its pharmaceutical composition for carrying out the methods of the present disclosure is affixed to the container or included in the kit. In some embodiments, the USP1 inhibitor is packaged in a unit dosage form. The kit may further comprise a device suitable for administering the USP1 inhibitor or its pharmaceutical composition according to the intended route of administration. In some embodiments, the present disclosure provides a kit comprising a USP1 inhibitor or its pharmaceutical composition, and instructions for administering the inhibitor or composition to a patient having cancer.

[0149] In some aspects, the present disclosure provides a pharmaceutical composition comprising a USP1 inhibitor (e.g., compound I or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal thereof) and a pharma- ceutically acceptable carrier, for use in treating cancer (e.g., a solid tumor).

[0150] In some aspects, the present disclosure provides a pharmaceutical composition comprising a USP1 inhibitor (e.g., Compound I or a pharma- ceutically acceptable salt, solvate, hydrate, or cocrystal thereof) and a pharma- ceutically acceptable carrier, for the manufacture of a medicament for the treatment of cancer (e.g., a solid tumor).

[0151] V. Preparation method of USP1 inhibitor The USP1 inhibitors for use in the uses and methods provided herein can be prepared by any method. Methods for synthesizing USP1 inhibitors are provided, for example, in International Publication No. 2020 / 132269 and PCT / US2021 / 057072 (each of which is incorporated herein by reference in its entirety).

[0152] In some embodiments, the USP1 inhibitor is prepared by a method comprising: a) adding a suitable amount of the compound of formula (I) to a suitable amount of a suitable solvent system to obtain a suspension; b) stirring the suspension; and c) recovering the solid product from step b). In some embodiments, a suitable pharma- ceutically acceptable acid is added during step a). In some embodiments, the suitable solvent system is selected from the group consisting of acetonitrile, acetone, cyclohexane, dichloromethane, dimethylacetamide, dimethylsulfoxide, ethanol, ethyl acetate, isopropyl alcohol, isopropyl acetate, methanol, methyl ethyl ketone, 4-methyl-2-pentanone, methyl tert-butyl ether, 2-methyltetrahydrofuran, n-heptane, n-methylpyrrolidone, tetrahydrofuran, toluene, water, and mixtures thereof. In some embodiments, the suitable solvent system is selected from the group consisting of ethyl acetate, n-heptane, and mixtures thereof.

[0153] In some embodiments, the USP1 inhibitor is prepared by a method comprising: a) dissolving a suitable amount of a compound of formula (I) in a suitable amount of a suitable solvent to obtain a solution; b) adding a suitable amount of a suitable anti-solvent; c) adding seed crystals of a compound of formula (I) in solid state form; d) stirring the resulting suspension; and e) recovering the solid product formed from step d). In some embodiments, the method further comprises adding a suitable pharma- ceutically acceptable acid during step a). In some embodiments, the method further comprises adding a suitable anti-solvent after step c) and before step d). In some embodiments, the suitable solvent and anti-solvent are selected from the group consisting of acetonitrile, acetone, cyclohexane, dichloromethane, dimethylacetamide, dimethylsulfoxide, ethanol, ethyl acetate, isopropyl alcohol, isopropyl acetate, methanol, methyl ethyl ketone, 4-methyl-2-pentanone, methyl tert-butyl ether, 2-methyltetrahydrofuran, n-heptane, n-methylpyrrolidone, tetrahydrofuran, toluene, water, and mixtures thereof. In some embodiments, the suitable solvent and anti-solvent are selected from the group consisting of ethyl acetate, n-heptane, and mixtures thereof. In some embodiments, the suitable solvent is ethyl acetate. In some embodiments, the suitable anti-solvent is n-heptane.

[0154] In some embodiments, the compound of formula (I) is added to the suitable solvent system at a temperature of about room temperature to about 100° C., or about room temperature to about 75° C., or about room temperature to about 50° C., or about room temperature to about 40° C. In some embodiments, the compound of formula (I) is added to the suitable solvent system at about room temperature.

[0155] In some embodiments, the USP1 inhibitor, which is a gentisic acid co-crystal of the compound of formula (I) in crystalline form 2, is prepared by a method comprising: a) adding a suitable amount of compound I and gentisic acid to a suitable amount of a suitable solvent system at room temperature to obtain a suspension; b) stirring the suspension from step a); and c) recovering the solid product from step b). In some embodiments, the suitable solvent system is selected from the group consisting of ethyl acetate, n-heptane, and mixtures thereof.

[0156] In some embodiments, the USP1 inhibitor, which is a gentisic acid co-crystal of the compound of formula (I) in crystalline form 2, is prepared by a method comprising: a) dissolving an appropriate amount of compound I and gentisic acid in an appropriate amount of an appropriate solvent at room temperature to obtain a solution; b) adding an appropriate amount of an appropriate anti-solvent; c) adding seed crystals of the gentisic acid co-crystal of compound I of formula (I) in crystalline form 2; d) stirring the resulting suspension; and e) recovering the solid product formed from step d). In some embodiments, the method further comprises adding an appropriate anti-solvent after step c) and before step d). In some embodiments, the appropriate solvent is ethyl acetate. In some embodiments, the appropriate anti-solvent is n-heptane.

[0157] In some embodiments, the USP1 inhibitor is a gentisic acid co-crystal of compound I of formula (I) in crystalline form 2, prepared by the methods disclosed herein. EXAMPLES

[0158] A. Abbreviations and Acronyms [Table 4]

[0159] B. Experimental Method Equipment conditions X-ray powder diffraction (XRPD) patterns were measured on an X'Pert 3 X-ray powder diffractometer using Cu-kα radiation. Each sample was spread in the center of a silicon holder with zero background. Tube voltage and amperage were set at 45 kV and 40 mA, respectively. Two-theta (2θ) continuous scans from 3° to 40° 2θ at 46.7 sec / step were used. XRPD analysis conditions are shown in Table 4 below. [Table 5]

[0160] Thermogravimetric analysis (TGA) data was collected using a TA Instruments TA Q5000 and a Discovery TGA 5500 TGA. The TGA analysis conditions are shown in Table 5 below. [Table 6]

[0161] Differential scanning calorimetry (DSC) data was collected using a TA Instruments TA Q2000 DSC. The DSC analysis conditions are shown in Table 6 below. [Table 7]

[0162] Polarized light microscopy (PLM) images were taken with a ZEISS Scope A1 microscope.

[0163] Example 1: Preparation and characterization of crystalline form A A. Preparation of Compounds of Formula (I) 6-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine was prepared according to the procedures disclosed in WO 2020 / 132269, the entirety of which is incorporated herein by reference.

[0164] To an ice-cold solution of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (1 eq.) in dimethylformamide (5 mL) was added sodium hydride (60% dispersion in mineral oil) (1.2 eq.) in portions and the reaction mixture was stirred at the same temperature for 10 min. To the resulting reaction mixture was added 2-iodopropane (1.20 eq.) and stirring was continued at room temperature for 16 h. The progress of the reaction was monitored by thin layer chromatography (TLC) and liquid chromatography mass spectrometry (LCMS). After completion, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2×200 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by preparative high performance liquid chromatography (HPLC) to obtain 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine of formula (I). The purified compound was then recrystallized from heptane and ethyl acetate using methods known to those skilled in the art.

[0165] B. Characterization The 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine of formula (I) obtained as described above was subjected to XRPD, TGA and DSC analysis using the above conditions. The obtained XRPD pattern, DSC profile and TGA profile are shown in Figures 1-2, respectively, and the XRPD peaks are shown in Table 1 above.

[0166] Based on the XRPD pattern shown in FIG. 1 and the XRPD peaks shown in Table 1(a and b), as well as the crystal structure and DSC and TGA profiles, 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine of formula (I) obtained as above was determined to be a crystalline hydrate and was named as crystalline form A.

[0167] C. Crystal structure determination Approximately 2.9 mg of crystalline form A was added to a 3 mL glass vial containing 0.5 mL of DCM / n-heptane (1:4, v / v) solvent mixture. The mixture was then shaken in an ultrasonic cleaner to aid in dissolution. The resulting suspension was filtered and the resulting clear solution was transferred to a clean 4 mL shell vial (44.6 mm x 14.65 mm). The shell vial was then sealed with a PE plug with one pinhole. The shell vial was then placed in a fume hood and allowed to slowly evaporate at room temperature. After one day of slow evaporation, block-shaped crystals were observed.

[0168] From the block crystal samples, suitable single crystals with good diffraction quality were selected and wrapped in Paratone-N (oil-based cryoprotectant). The crystals were mounted on mylar loops in random orientation and immersed in nitrogen flow at 120 K. Preliminary examination and data collection were performed on a Rigaku XtaLAB Synergy R (CuKα radiation, λ = 1.54184 Å) diffractometer and analyzed with the CrysAlisPro (V1.171.40.19a, Rigaku, 2018) software package. Using set angles of 49260 reflections in the range of 3.563° < θ < 75.668°, the cell parameters and orientation matrix for data collection were searched and refined (T-vector Dirax algorithm) by the CrysAlisPro (V1.171.40.19a, Rigaku, 2018) software. Data were collected at 120 K up to a minimum diffraction angle (θ) of 3.591° and a maximum diffraction angle (θ) of 76.011°. The completeness of the final point cloud is 100%. The average I / σ of the data is 69.7, with a best resolution cutoff of 0.79 Å.

[0169] Frames were integrated in CrysAlisPro (V1.171.40.19a, Rigaku, 2018). A total of 57,364 reflections were collected, of which 5292 were unique. Lorentzian and polarization corrections were applied to the data. Empirical absorption correction was performed with CrysAlisPro (V1.171.40.19a, Rigaku, 2018) using the spherical harmonica implemented in SCALE3 ABSPACK. The absorption coefficient μ of this material is 0.883 mm-1 at this wavelength (λ = 1.542 Å), with minimum and maximum transmittances of 0.94414 and 1.0000, respectively. The agreement rate for averaging was 5.19% on an intensity basis.

[0170] This structure is P2 1 / c In the space group, the ShelXT structure solver program uses intrinsic phasing to solve the F 2The data were refined with the ShelXL (Version 2018 / 3) refinement package using the full-matrix least-squares method above. All non-hydrogen atoms were refined anisotropically. Hydrogen atoms were calculated geometrically and refined using the riding model.

[0171] Calculated XRPD patterns were generated for copper ("Cu") irradiation using the Mercury program and atomic coordinates, space group, and unit cell parameters obtained from the single crystal structure. Crystal structure diagrams were generated by Olex2 and Diamond. Atomic thermal displacement ellipsoid diagrams were generated by ORTEP-III.

[0172] A suitable single crystal was separated from the block crystal and selected for single crystal X-ray diffraction data collection. The crystal system of the single crystal is monoclinic and the space group is P2. 1 / c The crystallographic data and refinement parameters are shown in Table 7. [Table 8]

[0173] As shown in Figure 3, the asymmetric unit of the single crystal structure consists of one molecule of the free base compound of formula (I) and a non-integer number of water molecules, suggesting that crystal form A is a hydrate. According to the thermal parameters, the number of water molecules in the asymmetric unit was liberally refined to be 0.42.

[0174] Example 2: Preparation and characterization of crystalline form 2 A. Preparation Method A: Approximately 40 mg of crystalline form A and 11.6 mg of gentisic acid were combined with 0.5 mL of EtOAc / n-heptane to obtain a suspension. The suspension was stirred at room temperature for 2 days and the solid material was isolated by vacuum filtration and dried under vacuum at room temperature. The resulting solid material can be used as a "seed" to prepare crystalline form 1 on a larger scale.

[0175] Method B: Approximately 500 mg of crystalline form A and 11.6 mg of gentisic acid were combined with 7 mL of EtOAc to obtain a solution. Then, 5.0 mL of n-heptane was added dropwise along with 10.2 mg of gentisic acid co-crystal "seeds" prepared according to Method A, and finally 8.0 mL of n-heptane was added to obtain a suspension. The suspension was stirred at room temperature for 2 days. The resulting solid material was isolated by vacuum filtration and dried under vacuum at room temperature.

[0176] B. Characterization The resulting solid material was subjected to XRPD, TGA and DSC analysis under the conditions described above. The resulting XRPD pattern, DSC profile and TGA profile are shown in Figures 2 and 3, respectively, and the XRPD peaks are shown in Table 1 above.

[0177] Based on the XRPD pattern shown in FIG. 4 and the XRPD peaks shown in Table 2, as well as the crystal structure and DSC and TGA profiles, the obtained solid material was determined to be a crystalline anhydrate of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine of formula (I) co-crystal with gentisic acid and was designated as crystalline Form 2.

[0178] C. Crystal structure determination Approximately 3.0 mg of crystalline Form 2 was added to a 3 mL glass vial containing 0.5 mL of THF / n-heptane (2:5, v / v) mixed solvent. The mixture was then shaken in an ultrasonic cleaner to aid in dissolution. The resulting suspension was filtered and the resulting clear solution was transferred to a clean 4 mL shell vial (44.6 mm x 14.65 mm). The shell vial was then sealed with a PE plug with one pinhole. The shell vial was then placed in a fume hood to allow slow evaporation at room temperature. After 6 days of slow evaporation, block-shaped crystals were observed.

[0179] From the block crystal samples, suitable single crystals with good diffraction quality were selected and wrapped in Paratone-N (oil-based cryoprotectant). The crystals were mounted on mylar loops in random orientation and immersed in nitrogen flow at 120 K. Preliminary examination and data collection were performed on a Rigaku XtaLAB Synergy R (CuKα radiation, λ = 1.54184 Å) diffractometer and analyzed with the CrysAlisPro (V1.171.40.19a, Rigaku, 2018) software package. Using set angles of 50053 reflections in the range of 3.539° < θ < 75.936°, the cell parameters and orientation matrix for data collection were searched and refined by the CrysAlisPro (V1.171.40.19a, Rigaku, 2018) software (T-vector Dirax algorithm). Data were collected at 120 K up to a minimum diffraction angle (θ) of 3.765° and a maximum diffraction angle (θ) of 76.018°. The completeness of the final point cloud is 100%. The average I / σ of the data is 75.8, with a best resolution cutoff of 0.79 Å.

[0180] Frames were integrated in CrysAlisPro (V1.171.40.19a, Rigaku, 2018). A total of 58850 reflections were collected, of which 6566 were unique. Lorentzian and polarization corrections were applied to the data. Empirical absorption corrections were performed with CrysAlisPro (V1.171.40.19a, Rigaku, 2018) using the spherical harmonica implemented in SCALE3 ABSPACK. The absorption coefficient μ of this material is 0.927 mm at this wavelength (λ = 1.542 Å). -1 where the minimum and maximum transmittances are 0.75213 and 1.0000, respectively. The agreement rate for the averaging was 3.94% on an intensity basis.

[0181] This structure is P2 1 / c In the space group, the ShelXT structure solver program uses intrinsic phasing to solve the F 2The above was refined with the ShelXL (Version 2018 / 3) refinement package using the full-matrix least-squares method. All non-hydrogen atoms were refined anisotropically. The hydrogen atoms (H2) connected to the oxygen atoms (O2) were freely determined and refined based on the Fourier Map. The other hydrogen atoms were geometrically calculated and refined using the riding model.

[0182] Calculated XRPD patterns were generated for copper ("Cu") irradiation using the Mercury program and atomic coordinates, space group, and unit cell parameters obtained from the single crystal structure. Crystal structure drawings were generated by Olex2 and Diamond. Thermal ellipsoids drawing was generated by ORTEP-III.

[0183] A suitable single crystal was isolated and selected from the block crystals for single crystal X-ray diffraction data collection. The crystal system of the single crystal was determined to be monoclinic and the space group was P2. 1 / c The crystallographic data and refinement parameters are shown in Table 8. [Table 9]

[0184] As shown in FIG. 6, the asymmetric unit of the single crystal structure consisted of one molecule of the neutral compound of formula (I) and one molecule of neutral gentisic acid, indicating that crystalline form 2 was indeed a cocrystal of the starting compound and gentisic acid.

[0185] Example 3: Pharmacokinetic study in mice A mouse pharmacokinetic (PK) study was conducted using crystalline form A of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine as disclosed herein and crystalline form 2 of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine as disclosed herein with gentisic acid co-crystal.

[0186] The PK study consisted of a single oral exposure study conducted in NOD / SCID female mice (approximately 6-8 weeks old, weighing 20-30 g at time of study) using a compound dose of 300 mg / kg and a dosing volume of 10 mL / kg. Mice were fasted overnight prior to dosing. After dosing, animals had free access to food and water.

[0187] Blood was serially collected from the dorsal metatarsal vein prior to dosing and at 0.25, 0.5, 1, 2, 4, 8, 24, 48 (crystalline form 2 only), and 72 hours (crystalline form 2 only) after PO dosing. Approximately 0.03 mL of blood was collected at each time point and centrifuged at 4000G for 5 minutes at 4°C to obtain plasma. Plasma samples were then stored in a freezer at -75±15°C prior to LC-MS / MS analysis.

[0188] The concentration of each compound in the plasma samples was then analyzed by LC-MS / MS. WinNonlin (PhoenixTM, version 6.1) or other similar software was used for PK calculations. Whenever possible, the following PK parameters were calculated from the plasma concentration versus time data: max , T max , T 1 / 2 , AUC inf , AUC last PK data were described using descriptive statistics, including means and standard deviations.

[0189] The results for crystalline form A are shown in Table 9 below and in FIG. [Table 10]

[0190] The results for crystalline Form 2 are shown in Table 10 below and in FIG. [Table 11]

[0191] Example 4: Distribution of crystalline Form 2 in mouse brain and plasma Female NOD SCID mice, aged 6-8 weeks and weighing 18-22 g, were purchased from Beijing Anikeeper Biotech Co, Ltd. The animals were allowed to acclimate to the environment for at least 7 days before the start of the study. The mice were administered crystalline form 2 by oral gavage at a dose of 100 mg / kg or 300 mg / kg for 28 days. 24 hours after 27 doses of the compound, three mice were euthanized with CO2. 4 hours after 28 doses of the compound, three mice were euthanized with CO2. Whole brains were harvested at each time point. In addition, approximately 0.03 mL of blood was collected at each time point and centrifuged at 4000G for 5 minutes at 4°C to obtain plasma. The samples were then stored in a freezer at -75±15°C prior to LC-MS / MS analysis. The compound concentrations (ng / g) in the brain homogenates and in the plasma (ng / ml) were then analyzed by LC-MS / MS method. PK data were described using descriptive statistics, including means and standard deviations.

[0192] Measurable drug levels were observed in brain tissue, as shown in Table 11 and Figure 9. No obvious accumulation was observed in the brain after repeated dosing. [Table 12]

[0193] Example 5. Distribution of crystalline form 2 in rat brain and plasma Male and female Sprague Dawley rats were purchased from Beijing Anikeeper Biotech Co, Ltd. The animals were habituated before the start of the study. Rats were administered crystalline form 2 at a single dose of 100 mg / kg by oral gavage. The rats were fasted overnight before dosing. The animals had access to food starting 2 hours after dosing and water ad libitum throughout the study period. Approximately 0.2 mL of blood was collected from the jugular vein at each time point and centrifuged at 4000G for 5 min at 4°C to obtain plasma. Samples were stored at -75±15°C in a freezer before LC-MS / MS analysis. Whole brains were harvested after hemoperfusion and flash frozen on dry ice before storage at -75±15°C. Whole brains were weighed and homogenized with water to achieve a tissue weight (g) to water volume (ml) ratio of 1:3 before LC-MS / MS analysis. The actual concentration was the measured value multiplied by the dilution factor. PK data were described using descriptive statistics, including means and standard deviations.

[0194] As shown in Table 12 and Figure 10, measurable drug levels were observed in brain tissue, and similar elimination profiles were observed between plasma and brain tissue, suggesting rapid equilibration between the systemic circulation and brain tissue. [Table 13]

[0195] Example 6: Phase 1 Administration of USP1 Inhibitors for the Treatment of Solid Tumors A Phase 1 dose escalation study of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (provided in the form of a gentisate cocrystal) is conducted in patients with advanced solid tumors. The dose escalation scheme is shown in Figure 11. The starting dose is 100 mg once daily (QD) in a 28-day cycle. The dose is administered orally. A first group of patients (e.g., 3 patients) is enrolled at this starting dose, and if none of the first group of patients experience dose-limiting toxicity (DLT; DLTs are listed in Table 1) in the first cycle (28 days), patients are enrolled at the next higher dose level. If any DLT is observed in the previous group of patients, more patients (e.g., 3 more patients) are treated at the same dose level. If no DLTs were observed in these patients, patients were then enrolled at the next highest dose level. If 2 or more DLTs were observed among 6 patients, the maximum tolerated dose (MTD) was defined as the previous dose level tested. If 2 or 3 of 3 patients experienced DLTs at any dose level, the previous level became the MTD. [Table 14]

[0196] Generally, patients are enrolled in Phase 1 trials if they meet the following "initiation criteria": · 18 years of age or older; · Life expectancy of 12 weeks or more; ·Resolved to grade 1 or lower toxicity or baseline toxicity (except for alopecia) from pretreatment (per National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) v5.0); ·Eastern Cooperative Oncology Group performance status of 0 or 1; · Adequate bone marrow function at baseline; · Adequate organ function at baseline; ·Continued treatment with strong or moderate CYP3A4 inhibitors or inducers is not required.

[0197] Patients typically also meet the following "additional criteria": ·Measurable or nonmeasurable disease by RECIST v1.1; Histologically or cytologically confirmed locally advanced (unresectable) or metastatic solid tumors meeting any of the following criteria: (a) have recurrent or progressed on standard treatment, (b) have disease for which no standard effective treatment exists, or (c) are not candidates for standard effective treatment.

[0198] Patients who meet any of the following "exclusion criteria" are typically not enrolled in Phase 1 trials: -Has had the following anti-cancer drug treatments: o Chemotherapy or small molecule targeted therapy <2 weeks prior to first dose of study treatment; o Antibody therapy less than 5 half-lives from the first dose of study treatment (or 4 weeks from the last treatment, whichever is shorter); oPD-1 or PD-L1 therapy <4 weeks after first dose of study treatment; o Invasive surgery requiring general anesthesia was performed <30 days after the first dose of study treatment; o Received chemotherapy with nitrosourea or mitomycin C within 45 days of the first dose of study treatment. o Radiation therapy (including radiofrequency ablation) less than 4 weeks prior to initiation of study treatment (Note: prior stereotactic body radiation therapy or local palliative radiation may be administered less than 2 weeks prior to the first dose of study treatment); Grade ≥2 toxicity, excluding alopecia related to prior treatment (i.e., chemotherapy, targeted therapy, radiation therapy, or surgery); · Prolongation of the QT / QTc interval using the Frederica method of QTc analysis (QTc interval >480 ms); · Seropositive for human immunodeficiency virus (HIV) 1 or 2, or acquired immune deficiency syndrome (AIDS), or active infection with hepatitis B virus or hepatitis C virus (HCV) (Note: Patients with positive HCV antibodies may be eligible in consultation with the Medical Monitor if HCV ribonucleic acid <[RNA] is undetectable by quantitative HCV RNA assay); Pregnant or breastfeeding women; - The patient has any other serious, acute or chronic medical condition or laboratory abnormality that may increase the risks associated with study participation or administration of the study medication, or that may compromise the interpretation of the study results, making the patient unsuitable for the study;

[0199] To demonstrate that 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine is effective in treating solid tumors, we evaluate the objective response rate (ORR based on Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) Investigator assessment), progression-free survival (PFS), duration of response (DOR based on RECIST v1.1 Investigator assessment), and time to response (TTR based on RECIST v1.1 Investigator assessment).

[0200] Example 7: Phase 2 Administration of USP1 Inhibitors for the Treatment of Solid Tumors A Phase 2 dose expansion study of the USP1 inhibitor 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (provided in the form of a gentisate cocrystal) will be conducted in patients with advanced solid tumors. In this study, the USP1 inhibitor will be administered until disease progression, investigator decision, withdrawal of consent, or other protocol-specified reason for discontinuing study treatment. There will be no intrapatient dose escalation in this study. The USP1 inhibitor will be studied at the MTD (or lower dose).

[0201] As described in Example 1, patients who generally fulfill the "initial criteria" and have measurable lesions according to RECIST v1.1 may be included in the Phase 2 study.

[0202] ORR based on RECIST v.1.1 by independent central radiologic review (ICRR) is evaluated to demonstrate that 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine is effective in treating solid tumors. Additionally, PFS, DOR, clinical benefit rate, and TTR (all based on RECIST v.1 by ICRR) are evaluated to demonstrate that 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine is effective in treating solid tumors. Furthermore, overall survival (OS) was assessed to demonstrate that 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine is effective in treating solid tumors.

[0203] Illustrative Examples of the Invention Illustrative examples of the present invention are given below.

[0204] In one example (I1), a method for treating a solid tumor in a human patient comprises administering to the patient about 1000 mg to about 2250 mg of the ubiquitin-specific processing protease 1 (USP1) inhibitor 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (Compound I), or a salt, solvate, hydrate, or cocrystal thereof, in an amount equivalent to about 1000 mg to about 2250 mg of Compound I. In one example (I2) of I1, about 1000 mg of the USP1 inhibitor, or a salt, solvate, hydrate, or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 1000 mg of the USP1 inhibitor. In one example of I1 (I3), the USP1 inhibitor is administered in an amount of about 1050 mg, or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 1050 mg of the USP1 inhibitor. In one example of I1 (I4), the USP1 inhibitor is administered in an amount of about 1100 mg, or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 1100 mg of the USP1 inhibitor. In one example of I1 (I5), the USP1 inhibitor is administered in an amount of about 1150 mg, or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 1150 mg of the USP1 inhibitor. In one example of I1 (I6), the USP1 inhibitor is administered in an amount of about 1200 mg, or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 1200 mg of the USP1 inhibitor. In one example of I1 (I7), the USP1 inhibitor is administered in an amount of about 1250 mg, or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 1250 mg of the USP1 inhibitor. In one example of I1 (I8), the USP1 inhibitor is administered in an amount of about 1300 mg, or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 1300 mg of the USP1 inhibitor. In one example of I1 (I9), the USP1 inhibitor is administered in an amount of about 1350 mg, or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 1350 mg of the USP1 inhibitor.In one example of I1 (I10), the USP1 inhibitor is administered in an amount of about 1400 mg, or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 1400 mg of the USP1 inhibitor. In one example of I1 (I11), the USP1 inhibitor is administered in an amount of about 1450 mg, or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 1450 mg of the USP1 inhibitor. In one example of I1 (I12), the USP1 inhibitor is administered in an amount of about 1500 mg, or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 1500 mg of the USP1 inhibitor. In one example of I1 (I13), the USP1 inhibitor is administered in an amount of about 1550 mg, or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 1550 mg of the USP1 inhibitor. In one example of I1 (I14), the USP1 inhibitor is administered in an amount of about 1600 mg, or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 1600 mg of the USP1 inhibitor. In one example of I1 (I15), the USP1 inhibitor is administered in an amount of about 1650 mg, or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 1650 mg of the USP1 inhibitor. In one example of I1 (I16), the USP1 inhibitor is administered in an amount of about 1700 mg, or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 1700 mg of the USP1 inhibitor. In one example of I1 (I17), the USP1 inhibitor is administered in an amount of about 1750 mg, or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 1750 mg of the USP1 inhibitor. In one example of I1 (I18), the USP1 inhibitor is administered in an amount of about 1800 mg, or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 1800 mg of the USP1 inhibitor. In one example of I1 (I19), the USP1 inhibitor is administered in an amount of about 1850 mg, or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 1850 mg of the USP1 inhibitor. In one example of I1 (I20), the USP1 inhibitor is administered in an amount of about 1900 mg, or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 1900 mg of the USP1 inhibitor.In one example of I1 (I21), the USP1 inhibitor is administered in an amount of about 1950 mg, or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 1950 mg of the USP1 inhibitor. In one example of I1 (I22), the USP1 inhibitor is administered in an amount of about 2000 mg, or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 2000 mg of the USP1 inhibitor. In one example of I1 (I23), the USP1 inhibitor is administered in an amount of about 2050 mg, or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 2050 mg of the USP1 inhibitor. In one example of I1 (I24), the USP1 inhibitor is administered in an amount of about 2100 mg, or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 2100 mg of the USP1 inhibitor. In one example of I1 (I25), the USP1 inhibitor is administered in an amount of about 2150 mg, or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 2150 mg of the USP1 inhibitor. In one example of I1 (I26), the USP1 inhibitor is administered in an amount of about 2200 mg, or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 2200 mg of the USP1 inhibitor. In one example of I1 (I27), the USP1 inhibitor is administered in an amount of about 2250 mg, or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 2250 mg of the USP1 inhibitor.

[0205] In one example (I28), a method for treating a solid tumor in a human patient comprises administering to the patient about 75 mg to about 1000 mg of the ubiquitin-specific processing protease 1 (USP1) inhibitor 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (Compound I), or a salt, solvate, hydrate, or cocrystal thereof, in an amount equivalent to about 75 mg to about 1000 mg of Compound I. In one example (I29) of I28, about 75 mg of the USP1 inhibitor, or a salt, solvate, hydrate, or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 75 mg of the USP1 inhibitor. In one example of I28 (I30), the USP1 inhibitor is administered in an amount of about 100 mg, or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 100 mg of the USP1 inhibitor. In one example of I28 (I31), the USP1 inhibitor is administered in an amount of about 150 mg, or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 150 mg of the USP1 inhibitor. In one example of I28 (I32), the USP1 inhibitor is administered in an amount of about 200 mg, or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 200 mg of the USP1 inhibitor. In one example of I28 (I33), the USP1 inhibitor is administered in an amount of about 250 mg, or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 250 mg of the USP1 inhibitor. In one example of I28 (I34), the USP1 inhibitor is administered in an amount of about 300 mg, or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 300 mg of the USP1 inhibitor. In one example of I28 (I35), the USP1 inhibitor is administered in an amount of about 350 mg, or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 350 mg of the USP1 inhibitor. In one example of I28 (I36), the USP1 inhibitor is administered in an amount of about 400 mg, or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 400 mg of the USP1 inhibitor.In one example of I28 (I37), the USP1 inhibitor is administered in an amount of about 450 mg, or a salt, solvate, hydrate, or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 450 mg of the USP1 inhibitor. In one example of I28 (I38), the USP1 inhibitor is administered in an amount of about 500 mg, or a salt, solvate, hydrate, or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 500 mg of the USP1 inhibitor. In one example of I28 (I39), the USP1 inhibitor is administered in an amount of about 550 mg, or a salt, solvate, hydrate, or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 550 mg of the USP1 inhibitor. In one example of I28 (I40), the USP1 inhibitor is administered in an amount of about 600 mg, or a salt, solvate, hydrate, or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 600 mg of the USP1 inhibitor. In one example of I28 (I41), the USP1 inhibitor is administered in an amount of about 650 mg, or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 650 mg of the USP1 inhibitor. In one example of I28 (I42), the USP1 inhibitor is administered in an amount of about 700 mg, or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 700 mg of the USP1 inhibitor. In one example of I28 (I43), the USP1 inhibitor is administered in an amount of about 750 mg, or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 750 mg of the USP1 inhibitor. In one example of I28 (I44), the USP1 inhibitor is administered in an amount of about 800 mg, or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 800 mg of the USP1 inhibitor. In one example of I28 (I45), the USP1 inhibitor is administered in an amount of about 850 mg, or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 850 mg of the USP1 inhibitor. In one example of I28 (I46), the USP1 inhibitor is administered in an amount of about 900 mg, or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 900 mg of the USP1 inhibitor. In one example of I28 (I47), the USP1 inhibitor is administered in an amount of about 950 mg, or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 950 mg of the USP1 inhibitor.In one example of I28 (I48), the USP1 inhibitor is administered in an amount equivalent to about 1000 mg, or a salt, solvate, hydrate or co-crystal of the USP1 inhibitor is administered in an amount equivalent to about 1000 mg of the USP1 inhibitor.

[0206] In one example (I49) of any one of I1-I48, the USP1 inhibitor, or a salt, solvate, hydrate, or cocrystal thereof, is administered about once daily.

[0207] In one example (I50) of any one of I1-I48, the USP1 inhibitor, or a salt, solvate, hydrate or cocrystal thereof, is administered as divided doses over the course of a day, wherein the administration may be divided into two doses, wherein the two doses may be the same or the two doses may be different.

[0208] In one example (I51) of any one of I1-I50, the USP1 inhibitor, or a salt, solvate, hydrate, or co-crystal thereof, is administered orally.

[0209] In one example (I52) of any one of I1-I51, the cancer is ovarian cancer. In one example (I53) of any one of I1-I52, the ovarian cancer is serous ovarian cancer. In one example (I54) of any one of I1-I51, the cancer is breast cancer. In one example (I55) of any one of I52-I54, the patient has previously received platinum-based chemotherapy. In one example (I56) of any one of I52-I54, the cancer is platinum-sensitive. In one example (I57) of any one of I52-I54, the cancer is platinum-resistant. In one example (I58) of any one of I54-I57, the breast cancer is human epidermal growth factor receptor 2 (HER2) negative. In one example (I59) of any one of I54-I58, the breast cancer is triple-negative breast cancer.

[0210] In one example (I60) of any one of I1 to I59, the cancer has a mutation in BRCA1. In one example (I61) of any one of I1 to I60, the cancer has a mutation in BRCA2.

[0211] In one example (I62) of any one of I54 to I61, the breast cancer is a germline breast cancer susceptibility gene mutation (gBRCAm) breast cancer. In one example (I63) of any one of I54 to I62, the breast cancer is metastatic.

[0212] In one example (I64) of any one of I1-I63, the patient has previously been treated with at least one systemic chemotherapy for metastatic disease.

[0213] In one example (I65) of any one of I1 to I51, the cancer is selected from the group consisting of a DNA damage repair pathway deficient cancer, a homologous recombination deficient cancer, a cancer comprising cancer cells having a mutation in the gene encoding p53, and a cancer comprising cancer cells having a loss-of-function mutation in the gene encoding p53.

[0214] In one example (I66) of any one of I1-I51, the cancer is selected from the group consisting of lung cancer, non-small cell lung cancer (NSCLC), colon cancer, bladder cancer, osteosarcoma, ovarian cancer, skin cancer, and breast cancer.

[0215] In one example (I67) of any one of I1-I66, the cancer comprises cancer cells with elevated levels of RAD18 protein and / or RAD18 mRNA. In one example (I68) of any one of I1-I67, the cancer comprises cancer cells with elevated levels of RAD51 protein and / or RAD51 mRNA. In one example (I69) of I68, the elevated levels of RAD51 are elevated levels of RAD51 protein foci. In one example (I70) of I68, at least 10% of cells in the S / G2 phase of the cell cycle in a sample obtained from the cancer are RAD51 positive.

[0216] In one example (I71) of any one of I1 to I70, the cancer has recurred.

[0217] In one example (I72) of any one of I1 to I71, the patient has previously been treated with a PARP inhibitor (PARPi). In one example (I73) of any one of I1 to I72, the cancer is a PARP inhibitor resistant or refractory cancer.

[0218] In one example (I74) of any one of I1-I73, compound I is administered as a co-crystal with a pharma- ceutically acceptable acid. In one example (I75) of I74, the pharma-ceutically acceptable acid is gentisic acid.

[0219] In one example (I76) of any one of I1-I75, the USP1 inhibitor, or a salt, solvate, hydrate, or cocrystal thereof, is administered at least three times, at least four times, or at least five times.

[0220] In one example (I77) of any one of I1-I75, the USP1 inhibitor, or a salt, solvate, hydrate, or cocrystal thereof is administered for at least 10 days, at least 15 days, at least 20 days, at least 25 days, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 1 year, at least 18 months, or at least 2 years.

[0221] In one example (I78), the USP1 inhibitor 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (Compound I), or a salt, solvate, hydrate, or co-crystal thereof, is for use in any one of the methods I1-I77.

Claims

1. 1. A method of treating a solid tumor in a human patient, comprising administering to the patient from about 75 mg to about 2250 mg of the ubiquitin-specific processing protease 1 (USP1) inhibitor 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (Compound I), or a salt, solvate, hydrate, or co-crystal thereof, in an amount equivalent to about 75 mg to about 2250 mg of Compound I.

2. 1. A method of treating a solid tumor in a human patient, comprising administering to the patient about 1000 mg to about 2250 mg of the ubiquitin-specific processing protease 1 (USP1) inhibitor 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (Compound I), or a salt, solvate, hydrate, or co-crystal thereof, in an amount equivalent to about 1000 mg to about 2250 mg of Compound I.

3. the USP1 inhibitor is administered in an amount of about 1000 mg, or a salt, solvate, hydrate, or co-crystal of the USP1 inhibitor equivalent to about 1000 mg of the USP1 inhibitor; the USP1 inhibitor is administered in an amount of about 1050 mg, or a salt, solvate, hydrate, or co-crystal of the USP1 inhibitor equivalent to about 1050 mg of the USP1 inhibitor; the USP1 inhibitor is administered in an amount of about 1100 mg, or a salt, solvate, hydrate, or co-crystal of the USP1 inhibitor equivalent to about 1100 mg of the USP1 inhibitor; the USP1 inhibitor is administered in an amount of about 1150 mg, or a salt, solvate, hydrate, or co-crystal of the USP1 inhibitor equivalent to about 1100 mg of the USP1 inhibitor; or a salt, solvate, hydrate or co-crystal of the USP1 inhibitor is administered in an amount equivalent to about 1150 mg of the USP1 inhibitor; or about 1200 mg of the USP1 inhibitor, or a salt, solvate, hydrate or co-crystal of the USP1 inhibitor is administered in an amount equivalent to about 1200 mg of the USP1 inhibitor; or about 1250 mg of the USP1 inhibitor, or a salt, solvate, hydrate or co-crystal of the USP1 inhibitor is administered in an amount equivalent to about 1250 mg of the USP1 inhibitor; or about 1300 mg of the USP1 inhibitor, or a salt, solvate, hydrate or co-crystal of the USP1 inhibitor is administered in an amount equivalent to about 1300 mg of the USP1 inhibitor. about 1300 mg of the USP1 inhibitor, or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 1350 mg of the USP1 inhibitor; about 1400 mg of the USP1 inhibitor, or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 1400 mg of the USP1 inhibitor; about 1450 mg of the USP1 inhibitor, or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 1400 mg of the USP1 inhibitor. the USP1 inhibitor is administered in an amount equivalent to about 1500 mg, or a salt, solvate, hydrate or co-crystal of the USP1 inhibitor is administered in an amount equivalent to about 1500 mg of the USP1 inhibitor; the USP1 inhibitor is administered in an amount equivalent to about 1550 mg, or a salt, solvate, hydrate or co-crystal of the USP1 inhibitor is administered in an amount equivalent to about 1550 mg of the USP1 inhibitor; the USP1 inhibitor is administered in an amount equivalent to about 1600 mg, or a salt, solvate, hydrate or co-crystal of the USP1 inhibitor is administered in an amount equivalent to about 1600 mg of the USP1 inhibitor;about 1650 mg of the USP1 inhibitor, or an amount of a salt, solvate, hydrate or co-crystal of the USP1 inhibitor equivalent to about 1650 mg of the USP1 inhibitor; about 1700 mg of the USP1 inhibitor, or an amount of a salt, solvate, hydrate or co-crystal of the USP1 inhibitor equivalent to about 1700 mg of the USP1 inhibitor; about 1750 mg of the USP1 inhibitor, or an amount of a salt, solvate, hydrate or co-crystal of the USP1 inhibitor equivalent to about 1750 mg of the USP1 inhibitor; about 1800 mg of the USP1 inhibitor, or an amount of a salt, solvate, hydrate or co-crystal of the USP1 inhibitor equivalent to about 1750 mg of the USP1 inhibitor. a salt, solvate, hydrate or co-crystal of a P1 inhibitor is administered in an amount equivalent to about 1800 mg of said USP1 inhibitor; about 1850 mg of said USP1 inhibitor, or a salt, solvate, hydrate or co-crystal of said USP1 inhibitor is administered in an amount equivalent to about 1850 mg of said USP1 inhibitor; about 1900 mg of said USP1 inhibitor, or a salt, solvate, hydrate or co-crystal of said USP1 inhibitor is administered in an amount equivalent to about 1900 mg of said USP1 inhibitor; about 1950 mg of said USP1 inhibitor, or a salt, solvate, hydrate or co-crystal of said USP1 inhibitor is administered the USP1 inhibitor is administered in an amount equivalent to about 1950 mg; the USP1 inhibitor is administered in an amount equivalent to about 2000 mg, or a salt, solvate, hydrate, or co-crystal of the USP1 inhibitor is administered in an amount equivalent to about 2000 mg; the USP1 inhibitor is administered in an amount equivalent to about 2050 mg, or a salt, solvate, hydrate, or co-crystal of the USP1 inhibitor is administered in an amount equivalent to about 2050 mg; the USP1 inhibitor is administered in an amount equivalent to about 2100 mg, or a salt, solvate, hydrate, or co-crystal of the USP1 inhibitor is administered in an amount equivalent to about 2100 mg. The method according to claim 1 or 2, wherein the USP1 inhibitor is administered in an amount of about 2150 mg, or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 2150 mg of the USP1 inhibitor; the USP1 inhibitor is administered in an amount of about 2200 mg, or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 2200 mg of the USP1 inhibitor; or the USP1 inhibitor is administered in an amount of about 2250 mg, or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 2250 mg of the USP1 inhibitor.

4. 1. A method of treating a solid tumor in a human patient, comprising administering to the patient about 75 mg to about 1000 mg of the ubiquitin-specific processing protease 1 (USP1) inhibitor 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (Compound I), or a salt, solvate, hydrate, or co-crystal thereof, in an amount equivalent to about 75 mg to about 1000 mg of Compound I.

5. about 75 mg of the USP1 inhibitor, or an amount of a salt, solvate, hydrate or co-crystal of the USP1 inhibitor equivalent to about 75 mg of the USP1 inhibitor; about 100 mg of the USP1 inhibitor, or an amount of a salt, solvate, hydrate or co-crystal of the USP1 inhibitor equivalent to about 100 mg of the USP1 inhibitor; about 150 mg of the USP1 inhibitor, or an amount of a salt, solvate, hydrate or co-crystal of the USP1 inhibitor equivalent to about 150 mg of the USP1 inhibitor; about 200 mg of the USP1 inhibitor; the salt, solvate, hydrate or co-crystal of the USP1 inhibitor is administered in an amount equivalent to about 200 mg of the USP1 inhibitor; the USP1 inhibitor is administered in an amount equivalent to about 250 mg, or the USP1 inhibitor is administered in an amount equivalent to about 250 mg of the USP1 inhibitor; the USP1 inhibitor is administered in an amount equivalent to about 300 mg, or the USP1 inhibitor is administered in an amount equivalent to about 300 mg of the USP1 inhibitor; the USP1 inhibitor is administered in an amount equivalent to about 350 mg, or the USP1 inhibitor is administered in an amount equivalent to about 300 mg of the USP1 inhibitor. about 400 mg of the USP1 inhibitor, or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 400 mg of the USP1 inhibitor; about 450 mg of the USP1 inhibitor, or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 450 mg of the USP1 inhibitor; about 500 mg of the USP1 inhibitor, or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 500 mg of the USP1 inhibitor. about 500 mg of the USP1 inhibitor is administered; about 550 mg of the USP1 inhibitor, or a salt, solvate, hydrate or co-crystal of the USP1 inhibitor is administered in an amount equivalent to about 550 mg of the USP1 inhibitor; about 600 mg of the USP1 inhibitor, or a salt, solvate, hydrate or co-crystal of the USP1 inhibitor is administered in an amount equivalent to about 600 mg of the USP1 inhibitor; about 650 mg of the USP1 inhibitor, or a salt, solvate, hydrate or co-crystal of the USP1 inhibitor is administered in an amount equivalent to about 650 mg of the USP1 inhibitor;about 700 mg of the USP1 inhibitor, or a salt, solvate, hydrate or co-crystal of the USP1 inhibitor is administered in an amount equivalent to about 700 mg of the USP1 inhibitor; about 750 mg of the USP1 inhibitor, or a salt, solvate, hydrate or co-crystal of the USP1 inhibitor is administered in an amount equivalent to about 750 mg of the USP1 inhibitor; about 800 mg of the USP1 inhibitor, or a salt, solvate, hydrate or co-crystal of the USP1 inhibitor is administered in an amount equivalent to about 800 mg of the USP1 inhibitor; about 850 mg of the USP1 inhibitor, or a salt, solvate, hydrate or co-crystal of the USP1 inhibitor is administered in an amount equivalent to about 750 mg of the USP1 inhibitor. The method according to claim 1 or 4, wherein the USP1 inhibitor is administered in an amount equivalent to about 850 mg; the USP1 inhibitor is administered in an amount equivalent to about 900 mg, or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 900 mg; the USP1 inhibitor is administered in an amount equivalent to about 950 mg, or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 950 mg; or the USP1 inhibitor is administered in an amount equivalent to about 1000 mg, or a salt, solvate, hydrate or cocrystal of the USP1 inhibitor is administered in an amount equivalent to about 1000 mg.

6. The method of any one of claims 1 to 5, wherein the USP1 inhibitor, or a salt, solvate, hydrate, or co-crystal thereof, is administered about once daily.

7. 6. The method of any one of claims 1 to 5, wherein the USP1 inhibitor, or a salt, solvate, hydrate or co-crystal thereof, is administered as a divided dose over the course of a day, which may be divided into two doses, which may be the same or which may be different.

8. The method of any one of claims 1 to 7, wherein the USP1 inhibitor, or a salt, solvate, hydrate or co-crystal thereof, is administered orally.

9. The method of any one of claims 1 to 8, wherein the cancer is ovarian cancer.

10. 10. The method of claim 9, wherein the ovarian cancer is serous ovarian cancer.

11. The method according to any one of claims 1 to 8, wherein the cancer is breast cancer.

12. The method of any one of claims 9 to 11, wherein the patient has previously received platinum-based chemotherapy.

13. The method of any one of claims 9 to 11, wherein the cancer is platinum sensitive.

14. The method of any one of claims 9 to 11, wherein the cancer is platinum resistant.

15. The method according to any one of claims 11 to 14, wherein the breast cancer is human epidermal growth factor receptor 2 (HER2) negative.

16. The method according to any one of claims 11 to 15, wherein the breast cancer is triple-negative breast cancer.

17. The method of any one of claims 1 to 16, wherein the cancer has a mutation in BRCA1.

18. The method of any one of claims 1 to 17, wherein the cancer has a mutation in BRCA2.

19. The method according to any one of claims 11 to 18, wherein the breast cancer is germline breast cancer susceptibility gene mutation (gBRCAm) breast cancer.

20. The method of any one of claims 11 to 19, wherein the breast cancer is metastatic.

21. The method of any one of claims 1 to 20, wherein the patient has previously been treated with at least one systemic chemotherapy regimen for metastatic disease.

22. The method according to any one of claims 1 to 8, wherein the cancer is selected from the group consisting of a DNA damage repair pathway deficient cancer, a homologous recombination deficient cancer, a cancer comprising cancer cells having a mutation in a gene encoding p53, and a cancer comprising cancer cells having a loss-of-function mutation in a gene encoding p53.

23. The method of any one of claims 1 to 8, wherein the cancer is selected from the group consisting of lung cancer, non-small cell lung cancer (NSCLC), colon cancer, bladder cancer, osteosarcoma, ovarian cancer, skin cancer, and breast cancer.

24. The method of any one of claims 1 to 23, wherein the cancer comprises cancer cells that have elevated levels of RAD18 protein and / or RAD18 mRNA.

25. The method of any one of claims 1 to 24, wherein the cancer comprises cancer cells that have elevated levels of RAD51 protein and / or RAD51 mRNA.

26. 26. The method of claim 25, wherein the elevated level of RAD51 is an elevated level of RAD51 protein foci.

27. 26. The method of claim 25, wherein at least 10% of cells in the S / G2 phase of the cell cycle in a sample obtained from the cancer are RAD51 positive.

28. The method of any one of claims 1 to 27, wherein the cancer has recurred.

29. The method of any one of claims 1 to 28, wherein the patient has previously been treated with a PARP inhibitor (PARPi).

30. The method according to any one of claims 1 to 29, wherein the cancer is a PARP inhibitor-resistant or refractory cancer.

31. The method of any one of claims 1 to 30, wherein Compound I is administered as a co-crystal with a pharma- ceutically acceptable acid.

32. 32. The method of claim 31 , wherein the pharma- ceutically acceptable acid is gentisic acid.

33. 33. The method of any one of claims 1 to 32, wherein the USP1 inhibitor, or a salt, solvate, hydrate, or co-crystal thereof, is administered at least three times, at least four times, or at least five times.

34. 33. The method of any one of claims 1 to 32, wherein the USP1 inhibitor, or a salt, solvate, hydrate or co-crystal thereof is administered for at least 10 days, at least 15 days, at least 20 days, at least 25 days, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 1 year, at least 18 months, or at least 2 years.

35. 35. The USP1 inhibitor 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (Compound I) or a salt, solvate, hydrate or co-crystal thereof for use in the method according to any one of claims 1 to 34.

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